Discovery.ucl.ac.uk
Gene therapy using haematopoietic stem and progenitor cells Giuliana Ferrari1,2, Adrian J. Thrasher3 and Alessandro Aiuti1,2,4,?1Vita-Salute San Raffaele University, Milan, Italy2San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy3Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK and Great Ormond Street Hospital NHS Trust, London, UK4Pediatric Immunohematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy?Email: alessandro.aiuti@hsr.itAbstractHaematopoietic stem and progenitor cell (HSPC) gene therapy has emerged as an effective treatment modality for monogenic disorders of the blood system such as primary immunodeficiencies and β-thalassemia. Medicinal products based on autologous HSPCs corrected using lentiviral and gammaretroviral vectors have now been approved for clinical use and the site-specific genome modification of HSPCs using gene editing techniques such as CRISPR/Cas9 has shown great clinical promise. Preclinical studies have shown engineered HSPCs could also be used to cross-correct non-hematopoietic cells in neurodegenerative metabolic diseases. Here, we review the most recent advances in HSPC gene therapy and discuss emerging strategies for using HSPC gene therapy for a range of diseases. [H1] Introduction Haematopoietic stem cell transplantation (HSCT) has been a routine procedure for treating inborn errors of metabolism and the blood system for over 50 yearsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFiYW5ub248L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy
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ADDIN EN.CITE.DATA 3,4. Extraordinary progress has been made in allogeneic HSCT and it is now used for many genetic diseases in an increasing number of patients. Improvements have been made with regards to donor matching, strategies for more effective control of graft-versus-host disease (GVHD), more effective conditioning regimens and better management of toxicity and infections. However, the availability of immunocompatible donors with optimal human leukocyte antigen (HLA) genotype matching can limit its applicationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdHljenluc2tpPC9BdXRob3I+PFllYXI+MjAyMDwvWWVh
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ADDIN EN.CITE.DATA 5 and morbidity owing to GVHD remains as a result of using unmatched donors. As a result, gene therapy techniques based on the genetic modification of autologous HSPCs have been explored. Autologous HSPC gene therapy has been investigated for the prevention or treatment monogenic disorders associated with altered blood cell maturation and function, such as diseases of the innate and adaptive immune systems, red blood cell disorders, platelet disorders and bone marrow failure syndromesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdW5iYXI8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 6-8. HSPC gene therapy techniques to date have employed ex vivo gene transfer, through transduction of the patients’ own HSPCs with a vectors carrying one or more copies of a therapeutic gene ADDIN EN.CITE <EndNote><Cite><Author>Naldini</Author><Year>2019</Year><RecNum>694</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>694</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">694</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Naldini, L.</author></authors></contributors><auth-address>San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Hospital and Research Institute, "Vita - Salute San Raffaele" University Medical School, Milan, Italy naldini.luigi@hsr.it.</auth-address><titles><title>Genetic engineering of hematopoiesis: current stage of clinical translation and future perspectives</title><secondary-title>EMBO molecular medicine</secondary-title><alt-title>EMBO Mol Med</alt-title></titles><alt-periodical><full-title>EMBO Mol Med</full-title></alt-periodical><pages>e99858</pages><volume>11</volume><number>3</number><edition>2019/01/24</edition><dates><year>2019</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1757-4684 (Electronic)
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ADDIN EN.CITE.DATA 15,16. The development of self-inactivating lentiviral vectors as a delivery platform ADDIN EN.CITE <EndNote><Cite><Author>Naldini</Author><Year>2019</Year><RecNum>694</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>694</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">694</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Naldini, L.</author></authors></contributors><auth-address>San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Hospital and Research Institute, "Vita - Salute San Raffaele" University Medical School, Milan, Italy naldini.luigi@hsr.it.</auth-address><titles><title>Genetic engineering of hematopoiesis: current stage of clinical translation and future perspectives</title><secondary-title>EMBO molecular medicine</secondary-title><alt-title>EMBO Mol Med</alt-title></titles><alt-periodical><full-title>EMBO Mol Med</full-title></alt-periodical><pages>e99858</pages><volume>11</volume><number>3</number><edition>2019/01/24</edition><dates><year>2019</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1757-4684 (Electronic)
1757-4676 (Linking)</isbn><accession-num>30670463</accession-num><work-type>Review</work-type><urls><related-urls><url> has since enabled more effective and safe insertion of therapeutic genes into HSPCs.Over the past two decades, advances in our understanding of disease biology and gene transfer technology have been translated into remarkable clinical successes (Fig. 2). As a result, the field has attracted significant commercial interest and two products have secured regulatory approval by the EMA in Europe — namely Strimvelis for use in ADA-SCID and Zynteglo for use in patients over 12 years old with transfusion-dependent β-thalassaemia (TDT) — with several others expected to follow in both Europe and the United States in the next five years. More than 300 patients have now been treated using HSPC gene therapy in clinical trials and robust evidence for the durability of corrected HSPC treatments and their long-term safety and clinical efficacy have been observed for PIDs including SCID-X1, ADA-SCID, Wiskott–Aldrich syndrome, chronic granulomatous disease [G] (CGD), β-thalassaemia, metachromatic leukodystrophy (MLD) and X-linked adrenoleukodystrophy (X-ALD) (Table 1).Here, we review the most recent advances in HSPC gene therapy. We begin with an overview of the ex vivo gene transfer process, from HSPC collection and genetic modification to engraftment and long-term clonal tracking. We discuss recent technological developments in gene editing, which will help move the field forward to the next generation of medicinal products, broadening the field of application to disorders not amenable to current gene addition approaches. Finally, we discuss the application of HSPC gene therapy for different diseases, including the use of HSPCs as delivery vehicles for therapeutic proteins, and conclude by considering remaining challenges in the field and future perspectives.[H1] Ex vivo gene transfer[H2] HSPC collection Autologous HSPCs are collected either through multiple aspirations from the iliac crests, or leukapheresis [G] following the administration of mobilizing agents [G] (Fig. 3) and collected material is enriched for CD34+ cells. Both procedures yield a mixture of non-engrafting cells and an heterogenous population of primitive and lineage-committed HSPCs that includes short-term repopulating haematopoietic progenitors contributing to early reconstitution and a very small fraction of long-term repopulating haematopoietic stem cells (HSCs) that take longer to restore haematopoiesis (Fig. 1). The relative composition of HSCs and haematopoeitic progenitor cells (HPCs) in the collected material depends on the collection method, disease background, age and the mobilization procedurePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaG9ybmxleTwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+
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ADDIN EN.CITE.DATA 22, although in-depth comparative studies between the two sources are lacking. However, as leukapheresis provides more HSPCs than bone marrow harvest per donor and allows for faster hematopoietic reconstitution ADDIN EN.CITE <EndNote><Cite><Author>Gertz</Author><Year>2010</Year><RecNum>817</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>817</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1593431573">817</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gertz, M. A.</author></authors></contributors><auth-address>Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA. gertz.morie@mayo.edu</auth-address><titles><title>Current status of stem cell mobilization</title><secondary-title>Br J Haematol</secondary-title></titles><pages>647-62</pages><volume>150</volume><number>6</number><edition>2010/07/20</edition><keywords><keyword>Antigens, CD34/blood</keyword><keyword>Antineoplastic Agents/therapeutic use</keyword><keyword>Filgrastim</keyword><keyword>Granulocyte Colony-Stimulating Factor/administration & dosage</keyword><keyword>Growth Substances/administration & dosage</keyword><keyword>Hematopoietic Stem Cell Mobilization/*methods</keyword><keyword>Hematopoietic Stem Cell Transplantation/*methods</keyword><keyword>Humans</keyword><keyword>Lymphoma, Non-Hodgkin/*therapy</keyword><keyword>Multiple Myeloma/*therapy</keyword><keyword>Peripheral Blood Stem Cell Transplantation/methods</keyword><keyword>Recombinant Proteins</keyword></keywords><dates><year>2010</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1365-2141 (Electronic)
0007-1048 (Linking)</isbn><accession-num>20636438</accession-num><urls><related-urls><url> it is now the preferred procedure. G-CSF was the first mobilizing agent used for allogeneic transplantation; however, as some patients have a limited mobilization response to G-CSF ADDIN EN.CITE <EndNote><Cite><Author>Gertz</Author><Year>2010</Year><RecNum>817</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>817</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1593431573">817</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gertz, M. A.</author></authors></contributors><auth-address>Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA. gertz.morie@mayo.edu</auth-address><titles><title>Current status of stem cell mobilization</title><secondary-title>Br J Haematol</secondary-title></titles><pages>647-62</pages><volume>150</volume><number>6</number><edition>2010/07/20</edition><keywords><keyword>Antigens, CD34/blood</keyword><keyword>Antineoplastic Agents/therapeutic use</keyword><keyword>Filgrastim</keyword><keyword>Granulocyte Colony-Stimulating Factor/administration & dosage</keyword><keyword>Growth Substances/administration & dosage</keyword><keyword>Hematopoietic Stem Cell Mobilization/*methods</keyword><keyword>Hematopoietic Stem Cell Transplantation/*methods</keyword><keyword>Humans</keyword><keyword>Lymphoma, Non-Hodgkin/*therapy</keyword><keyword>Multiple Myeloma/*therapy</keyword><keyword>Peripheral Blood Stem Cell Transplantation/methods</keyword><keyword>Recombinant Proteins</keyword></keywords><dates><year>2010</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1365-2141 (Electronic)
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ADDIN EN.CITE.DATA 30,31 and followed by HIV-derived, self-inactivating (SIN) lentiviral vectors ADDIN EN.CITE <EndNote><Cite><Author>Naldini</Author><Year>1996</Year><RecNum>502</RecNum><DisplayText><style face="superscript">32</style></DisplayText><record><rec-number>502</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">502</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Naldini, L.</author><author>Blomer, U.</author><author>Gallay, P.</author><author>Ory, D.</author><author>Mulligan, R.</author><author>Gage, F. H.</author><author>Verma, I. M.</author><author>Trono, D.</author></authors></contributors><auth-address>Salk Institute, La Jolla, CA 92037, USA.</auth-address><titles><title>In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector</title><secondary-title>Science</secondary-title></titles><pages>263-7</pages><volume>272</volume><number>5259</number><edition>1996/04/12</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Animals</keyword><keyword>Base Sequence</keyword><keyword>Brain/cytology/virology</keyword><keyword>Cell Division</keyword><keyword>Cells, Cultured</keyword><keyword>Female</keyword><keyword>*Gene Transfer Techniques</keyword><keyword>Genetic Therapy</keyword><keyword>*Genetic Vectors</keyword><keyword>HIV/*genetics/physiology</keyword><keyword>HeLa Cells</keyword><keyword>Humans</keyword><keyword>Macrophages/cytology/virology</keyword><keyword>Molecular Sequence Data</keyword><keyword>Neurons/cytology/virology</keyword><keyword>Plasmids</keyword><keyword>Rats</keyword><keyword>Transfection</keyword><keyword>Virus Integration</keyword></keywords><dates><year>1996</year><pub-dates><date>Apr 12</date></pub-dates></dates><isbn>0036-8075 (Print)
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ADDIN EN.CITE.DATA 34. Lentiviral vectors have become the most commonly-used vector for ex vivo HSPC gene therapy because of their good safety profile; lentiviral vectors preferentially integrate into gene bodies over promoters, reducing the potential for aberrant transcriptional activation (Fig. 4B). Further, in SIN vectors, the viral promoter located in the lentiviral vector LTR is inactivated upon integration into the genome, limiting transcriptional transactivation of cellular genes. Modifications in vector structure, including the deletion of promoter viral sequences in the LTRs and the splitting of viral protein genes across separate plasmids provided in trans during vector particle production have since contributed to a reduction in genotoxic risk associated with transcriptional transactivation and aided the production of replication-defective vector particlesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWFzY288L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 35. Although lentiviral vector-mediated gene therapy has an excellent clinical safety record, there remains a theoretical long-term risk of genotoxicity. In addition, the risks associated with high-dose chemotherapy — which is required in some cases for HSPC gene therapy — hamper the application of this approach for less severe conditions. There are also limitations that prevent the wider application of gene therapy approaches for genes that require physiological control of gene expression or gain-of-function mutations.[H2] Gene editing approaches Site-specific genome editing using programmable endonuclease platforms such as CRISPR–Cas9, transcription activator-like effector nucleases (TALENs) or zinc finger nucleases (ZFNs) ADDIN EN.CITE <EndNote><Cite><Author>Porteus</Author><Year>2019</Year><RecNum>666</RecNum><DisplayText><style face="superscript">36</style></DisplayText><record><rec-number>666</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">666</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Porteus, M. H.</author></authors></contributors><auth-address>From the Department of Pediatrics-Stem Cell Transplantation, Stanford University, Stanford, CA.</auth-address><titles><title>A New Class of Medicines through DNA Editing</title><secondary-title>The New England journal of medicine</secondary-title><alt-title>N Engl J Med</alt-title></titles><pages>947-959</pages><volume>380</volume><number>10</number><edition>2019/03/12</edition><keywords><keyword>CRISPR-Associated Protein 9</keyword><keyword>CRISPR-Cas Systems</keyword><keyword>Dna</keyword><keyword>Drug Discovery/*methods</keyword><keyword>Gene Editing/history/*methods</keyword><keyword>History, 20th Century</keyword><keyword>History, 21st Century</keyword></keywords><dates><year>2019</year><pub-dates><date>Mar 7</date></pub-dates></dates><isbn>1533-4406 (Electronic)
0028-4793 (Linking)</isbn><accession-num>30855744</accession-num><work-type>Historical Article
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ADDIN EN.CITE.DATA 37, ADDIN EN.CITE <EndNote><Cite><Author>Lombardo</Author><Year>2014</Year><RecNum>857</RecNum><DisplayText><style face="superscript">38</style></DisplayText><record><rec-number>857</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1600267827">857</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lombardo, A.</author><author>Naldini, L.</author></authors></contributors><auth-address>San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milan, Italy.</auth-address><titles><title>Genome editing: a tool for research and therapy: targeted genome editing hits the clinic</title><secondary-title>Nat Med</secondary-title></titles><periodical><full-title>Nat Med</full-title></periodical><pages>1101-3</pages><volume>20</volume><number>10</number><edition>2014/10/09</edition><keywords><keyword>Animals</keyword><keyword>Gene Targeting/*methods</keyword><keyword>Genetic Engineering</keyword><keyword>Genetic Therapy/*methods</keyword><keyword>Genome, Human</keyword><keyword>HIV Infections/genetics/therapy</keyword><keyword>Humans</keyword><keyword>Interleukin Receptor Common gamma Subunit/genetics</keyword><keyword>Mice</keyword><keyword>RNA Editing</keyword><keyword>Receptors, CCR5/genetics</keyword><keyword>Translational Medical Research</keyword><keyword>X-Linked Combined Immunodeficiency Diseases/genetics/therapy</keyword></keywords><dates><year>2014</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1546-170X (Electronic)
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ADDIN EN.CITE.DATA 40. HDR may not be as efficient in long-term HSCs as in progenitor cells because it mostly occurs in cell cycle phases (S/G2) incompatible with the HSC quiescent state and because of inefficient template uptake, which could limit the clinical translation of gene editing in diseases requiring a high frequency of gene-modified HSPCs such as lysosomal storage diseases. Chemical modification of single-strand guide RNA and innovations in the delivery systems of nucleases such as pre-assembled CRISPR-Cas9 RNPs and the use of donor templates based on AAV6 have increased the frequency of edited HSCs with promising results for future successful development and clinical applicationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XdTwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA 39,44-47. More recently, strategies to force cell cycle progression and to upregulate the expression of cellular components of the HDR machinery led to the successful increase of gene correction in up to 50% of in vivo repopulating HSCs ADDIN EN.CITE <EndNote><Cite><Author>Ferrari</Author><Year>2020</Year><RecNum>823</RecNum><DisplayText><style face="superscript">46</style></DisplayText><record><rec-number>823</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1594917943">823</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ferrari, S.</author><author>Jacob, A.</author><author>Beretta, S.</author><author>Unali, G.</author><author>Albano, L.</author><author>Vavassori, V.</author><author>Cittaro, D.</author><author>Lazarevic, D.</author><author>Brombin, C.</author><author>Cugnata, F.</author><author>Kajaste-Rudnitski, A.</author><author>Merelli, I.</author><author>Genovese, P.</author><author>Naldini, L.</author></authors></contributors><titles><title>Efficient gene editing of human long-term hematopoietic stem cells validated by clonal tracking</title><secondary-title>Nature Biotechnology</secondary-title></titles><volume>in press</volume><dates><year>2020</year><pub-dates><date>2020</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1038/s41587-020-0551-y</electronic-resource-num></record></Cite></EndNote>46.Proof of principle for the gene editing of HSPCs has been achieved in preclinical studiesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZXZlcjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 39,45,48,49, leading to two ongoing industry-sponsored clinical trials using ZFN and CRISPR-Cas9 technologies knocking-out BCL11A to address transfusion-dependent ?-thalassemia (TDT) and sickle cell disease (SCD), respectively (Table 1). BCL11A encodes a protein that represses the expression of HbF. Initial results from a patient with TDT and a patient with SCD showed good editing efficiency of HSPCs using CRISPR-Cas9 to disrupt BCL11A, increasing levels of total haemoglobin and fetal haemoglobin (HbF) over time in both patients, indicating successful engraftment of the edited cells ADDIN EN.CITE <EndNote><Cite><Author>Corbacioglu S</Author><Year>2020</Year><RecNum>822</RecNum><DisplayText><style face="superscript">50</style></DisplayText><record><rec-number>822</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1594828977">822</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corbacioglu S, Cappellini M.D., Chapin J., Chu-Osier N.,Fernandez C.M., Foell J., de la Fuente J., Grupp S.,Ho T.W., Kattamis A., Lekstrom- Himes J., Locatelli F., Lu Y., de Montalembert M., Rondelli D., Ross A., Shanbhag N., Sheth S. Soni S., Steinberg M., Frangoul H.</author></authors></contributors><titles><title>Initial safety and efficacy results with a single dose of autologous CRISPR-CAS9 modified CD34+ hematopietic stem and progenitor cells in transfusion-dependent ?-thalassemia and sickle cell disease</title><secondary-title>HemaSphere</secondary-title></titles><pages>101</pages><volume>4</volume><number>S1</number><num-vols>Supplement</num-vols><dates><year>2020</year></dates><work-type>Abstract</work-type><urls></urls><electronic-resource-num>10.1097/HS9.0000000000000404</electronic-resource-num></record></Cite></EndNote>50. SCD represents an ideal model for HDR gene editing approaches as it is caused by a single nucleotide mutation in a single gene. Studies using CRISPR-Cas9 to correct the SCD mutation — which is present in HBB, the gene encoding β-globin — showed HDR-mediated correction in isolated CD34+ cells was effective in vivo, but the frequency of corrected cells decreased after xenotransplantation to less than 10%, indicating differential targeting of progenitors versus repopulating HSCs could limit the clinical application of this approachPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZVdpdHQ8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 58. Gene editing technologies do have potential risks associated with off-target effects and DNA rearrangements such as chromosomal translocations and large deletions ADDIN EN.CITE <EndNote><Cite><Author>Kosicki</Author><Year>2018</Year><RecNum>739</RecNum><DisplayText><style face="superscript">59</style></DisplayText><record><rec-number>739</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">739</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kosicki, M.</author><author>Tomberg, K.</author><author>Bradley, A.</author></authors></contributors><auth-address>Wellcome Sanger Institute, Hinxton, UK.</auth-address><titles><title>Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements</title><secondary-title>Nature biotechnology</secondary-title><alt-title>Nat Biotechnol</alt-title></titles><alt-periodical><full-title>Nat Biotechnol</full-title></alt-periodical><pages>765-771</pages><volume>36</volume><number>8</number><edition>2018/07/17</edition><keywords><keyword>Animals</keyword><keyword>*CRISPR-Cas Systems</keyword><keyword>*DNA Breaks, Double-Stranded</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mutagenesis</keyword><keyword>Polymerase Chain Reaction/methods</keyword><keyword>*Sequence Deletion</keyword></keywords><dates><year>2018</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1546-1696 (Electronic)
1087-0156 (Linking)</isbn><accession-num>30010673</accession-num><work-type>Letter
Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>, which are difficult to predict in preclinical models. In the case of HbF reactivation, the lack of a marker could make the origin of an increase in HbF difficult to determine as increased HbF is usually observed as a consequence of the transplantation procedure in general, especially in patients with SCD or β-thalassaemiaPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxhbmVsbG88L0F1dGhvcj48WWVhcj4xOTg5PC9ZZWFy
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ADDIN EN.CITE.DATA 62-64 — which use a catalytically-impaired CRISPR/Cas9 carrying nickase activity but lacking DSB activity in association with a deaminase and reverse transcriptase, respectively — hold promise for efficient and possibly safer genome engineering, although most results have been obtained in cell lines and not in primary human cells. [H2] Cell culture and transduction In both vector-mediated gene transfer and gene editing approaches, the in vitro culture and manipulation of HSPCs can induce transcriptional responses and signaling events that may affect both primitive and gradually more committed cell populationsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QaXJhczwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 71, ADDIN EN.CITE <EndNote><Cite><Author>Schott</Author><Year>2019</Year><RecNum>755</RecNum><DisplayText><style face="superscript">72</style></DisplayText><record><rec-number>755</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">755</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schott, J. W.</author><author>Leon-Rico, D.</author><author>Ferreira, C. B.</author><author>Buckland, K. F.</author><author>Santilli, G.</author><author>Armant, M. A.</author><author>Schambach, A.</author><author>Cavazza, A.</author><author>Thrasher, A. J.</author></authors></contributors><auth-address>Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
Great Ormond Street Hospital NHS Foundation Trust, London WC1N 1EH, UK.</auth-address><titles><title>Enhancing Lentiviral and Alpharetroviral Transduction of Human Hematopoietic Stem Cells for Clinical Application</title><secondary-title>Molecular therapy. Methods & clinical development</secondary-title><alt-title>Mol Ther Methods Clin Dev</alt-title></titles><alt-periodical><full-title>Mol Ther Methods Clin Dev</full-title></alt-periodical><pages>134-147</pages><volume>14</volume><edition>2019/07/25</edition><dates><year>2019</year><pub-dates><date>Sep 13</date></pub-dates></dates><isbn>2329-0501 (Print)
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ADDIN EN.CITE.DATA 28,74 can enhance targeting of the vectors to HSPCs by enhancing vector particle attachment or entry, or acting on post-entry phases allowing for a higher level of integration. However, long-term clinical trials are needed to assess the efficacy of these drugs for improving the efficiency of HSPC engraftment.[H2] Patient conditioning Conditioning regimens using chemotherapeutic or immunosuppressant drugs aim to deplete a patient’s endogenous HSPC population in order to clear a niche for engraftment of corrected cells while mitigating toxicity. Conditioning can range from reduced intensity to myeloablative conditioning, [G] depending on the disease, the required level of transgene expression and the engraftment level required to reach the therapeutic threshold ADDIN EN.CITE <EndNote><Cite><Author>Bernardo</Author><Year>2016</Year><RecNum>527</RecNum><DisplayText><style face="superscript">75</style></DisplayText><record><rec-number>527</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">527</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bernardo, M. E.</author><author>Aiuti, A.</author></authors></contributors><auth-address>Scientific Institute HS Raffaele, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milano, Italy ; bernardo.mariaester@hsr.it.
Scientific Institute HS Raffaele, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milano, MI, Italy ; aiuti.alessandro@hsr.it.</auth-address><titles><title>The role of conditioning in hematopoietic stem cell gene therapy</title><secondary-title>Hum Gene Ther</secondary-title></titles><periodical><full-title>Hum Gene Ther</full-title></periodical><pages>741-748</pages><volume>27</volume><number>10</number><edition>2016/08/18</edition><dates><year>2016</year><pub-dates><date>Aug 16</date></pub-dates></dates><isbn>1557-7422 (Electronic)
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ADDIN EN.CITE.DATA 78. Toxicity associated with conditioning can be mitigated using pharmacokinetic techniques; for example, the toxicity of the alkylating agent busulfan is currently mitigated by serial evaluations of concentrations to determine the area under the curve (AUC) ADDIN EN.CITE <EndNote><Cite><Author>Bernardo</Author><Year>2016</Year><RecNum>527</RecNum><DisplayText><style face="superscript">75</style></DisplayText><record><rec-number>527</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">527</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bernardo, M. E.</author><author>Aiuti, A.</author></authors></contributors><auth-address>Scientific Institute HS Raffaele, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milano, Italy ; bernardo.mariaester@hsr.it.
Scientific Institute HS Raffaele, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milano, MI, Italy ; aiuti.alessandro@hsr.it.</auth-address><titles><title>The role of conditioning in hematopoietic stem cell gene therapy</title><secondary-title>Hum Gene Ther</secondary-title></titles><periodical><full-title>Hum Gene Ther</full-title></periodical><pages>741-748</pages><volume>27</volume><number>10</number><edition>2016/08/18</edition><dates><year>2016</year><pub-dates><date>Aug 16</date></pub-dates></dates><isbn>1557-7422 (Electronic)
1043-0342 (Linking)</isbn><accession-num>27530055</accession-num><urls><related-urls><url>, followed by dose adjustment.Infertility is a major risk of myeloablative chemotherapy that can be addressed by gonadal cryopreservation in childrenPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYWxsZTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 81. Recently, a phase I clinical study assessing the safety and tolerability of allogeneic transplantation in patients with SCID treated with an anti-CD117 antibody showed promising initial results with successful engraftment of donor cells ADDIN EN.CITE <EndNote><Cite><Author>Agarwal R.</Author><Year>2019</Year><RecNum>763</RecNum><DisplayText><style face="superscript">82</style></DisplayText><record><rec-number>763</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">763</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Agarwal R., Dvorak CC., Prohaska S., Long-Boyle J., Kwon HS., Brown JM., Weinberg KI., Guttman A., Logan AC., Weissman IL., Digiusto D., Cowan MJ., Parkman R., Roncarolo MGR., Shizuru Ja. </author></authors></contributors><titles><title>Toxicity-Free Hematopoietic Stem Cell Engraftment Achieved with Anti-CD117 Monoclonal Antibody Conditioning</title><secondary-title>Biology of Blood and Marrow Transplantation</secondary-title></titles><pages>S92</pages><volume>25</volume><number>3, Supplement</number><dates><year>2019</year></dates><urls></urls></record></Cite></EndNote>82. If proven to be safe and efficacious, these therapeutic antibodies could be used for conditions in which the risk of chemotherapy is deemed too high, or where the pre-existent inflammatory status of the bone marrow is further exacerbated by the effect of conventional conditioning regimens. The bone marrow microenvironment plays a key role in facilitating the engraftment and expansion of genetically-corrected cells. Recent studies found a defective bone marrow environment in β-thalassemia was associated with impaired HSC function that could negatively affect engraftmentPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DcmlwcGE8L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 86. In both cases, engraftment results in persistent expression of the transgene driven by the integrated vector, as assessed by immunological and/or biochemical monitoring. Correction of the disease phenotype has been reported in most treated patients, the degree of which usually correlates with levels of engraftment and transgene expression in vivo. The extent of correction of repopulating HSPCs has been variable among trials, ranging from 0.1% to 80%PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXNzYTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 77 of gene-modified HSPCs. The highest and most consistent levels of engraftment for various lineages have been observed in studies using HSPCs corrected using lentiviral vectors and a myeloablative patient conditioning strategy ADDIN EN.CITE <EndNote><Cite><Author>Naldini</Author><Year>2019</Year><RecNum>694</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>694</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">694</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Naldini, L.</author></authors></contributors><auth-address>San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Hospital and Research Institute, "Vita - Salute San Raffaele" University Medical School, Milan, Italy naldini.luigi@hsr.it.</auth-address><titles><title>Genetic engineering of hematopoiesis: current stage of clinical translation and future perspectives</title><secondary-title>EMBO molecular medicine</secondary-title><alt-title>EMBO Mol Med</alt-title></titles><alt-periodical><full-title>EMBO Mol Med</full-title></alt-periodical><pages>e99858</pages><volume>11</volume><number>3</number><edition>2019/01/24</edition><dates><year>2019</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1757-4684 (Electronic)
1757-4676 (Linking)</isbn><accession-num>30670463</accession-num><work-type>Review</work-type><urls><related-urls><url>. Engraftment failures have been associated with insufficient doses of HSPCs or insufficient transduction efficiency, a lack of patient conditioning or the presence of concomitant diseases such as underlying infections ADDIN EN.CITE <EndNote><Cite><Author>Bernardo</Author><Year>2016</Year><RecNum>527</RecNum><DisplayText><style face="superscript">75</style></DisplayText><record><rec-number>527</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">527</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bernardo, M. E.</author><author>Aiuti, A.</author></authors></contributors><auth-address>Scientific Institute HS Raffaele, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milano, Italy ; bernardo.mariaester@hsr.it.
Scientific Institute HS Raffaele, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milano, MI, Italy ; aiuti.alessandro@hsr.it.</auth-address><titles><title>The role of conditioning in hematopoietic stem cell gene therapy</title><secondary-title>Hum Gene Ther</secondary-title></titles><periodical><full-title>Hum Gene Ther</full-title></periodical><pages>741-748</pages><volume>27</volume><number>10</number><edition>2016/08/18</edition><dates><year>2016</year><pub-dates><date>Aug 16</date></pub-dates></dates><isbn>1557-7422 (Electronic)
1043-0342 (Linking)</isbn><accession-num>27530055</accession-num><urls><related-urls><url>, ADDIN EN.CITE <EndNote><Cite><Author>Bernardo</Author><Year>2016</Year><RecNum>527</RecNum><DisplayText><style face="superscript">75</style></DisplayText><record><rec-number>527</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">527</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bernardo, M. E.</author><author>Aiuti, A.</author></authors></contributors><auth-address>Scientific Institute HS Raffaele, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milano, Italy ; bernardo.mariaester@hsr.it.
Scientific Institute HS Raffaele, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milano, MI, Italy ; aiuti.alessandro@hsr.it.</auth-address><titles><title>The role of conditioning in hematopoietic stem cell gene therapy</title><secondary-title>Hum Gene Ther</secondary-title></titles><periodical><full-title>Hum Gene Ther</full-title></periodical><pages>741-748</pages><volume>27</volume><number>10</number><edition>2016/08/18</edition><dates><year>2016</year><pub-dates><date>Aug 16</date></pub-dates></dates><isbn>1557-7422 (Electronic)
1043-0342 (Linking)</isbn><accession-num>27530055</accession-num><urls><related-urls><url>
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ADDIN EN.CITE.DATA 91. MSCs are localized in the endosteum and around the sinusoidal vessels ADDIN EN.CITE <EndNote><Cite><Author>Kfoury</Author><Year>2015</Year><RecNum>782</RecNum><DisplayText><style face="superscript">92</style></DisplayText><record><rec-number>782</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1587044060">782</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kfoury, Y.</author><author>Scadden, D. T.</author></authors></contributors><auth-address>Center for Regenerative Medicine and MGH Cancer Center, Massachusetts General Hospital, Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Boston, MA 02114, USA.
Center for Regenerative Medicine and MGH Cancer Center, Massachusetts General Hospital, Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Boston, MA 02114, USA. Electronic address: david_scadden@harvard.edu.</auth-address><titles><title>Mesenchymal cell contributions to the stem cell niche</title><secondary-title>Cell Stem Cell</secondary-title><alt-title>Cell stem cell</alt-title></titles><periodical><full-title>Cell Stem Cell</full-title></periodical><alt-periodical><full-title>Cell Stem Cell</full-title></alt-periodical><pages>239-53</pages><volume>16</volume><number>3</number><keywords><keyword>Animals</keyword><keyword>Antigens, Differentiation/*metabolism</keyword><keyword>Bone Marrow Cells/cytology/*metabolism</keyword><keyword>Humans</keyword><keyword>Mesenchymal Stem Cells/cytology/*metabolism</keyword><keyword>Stem Cell Niche/*physiology</keyword></keywords><dates><year>2015</year><pub-dates><date>Mar 5</date></pub-dates></dates><isbn>1875-9777 (Electronic)
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ADDIN EN.CITE.DATA 95,96. MSCs have been used in the clinical setting to expand ex vivo HSPCsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBMaW1hPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48
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ADDIN EN.CITE.DATA 97 and a recent pilot study described the infusion of MSCs to facilitate HSPC engraftmentPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBMaW1hPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48
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ADDIN EN.CITE.DATA 100, ADDIN EN.CITE <EndNote><Cite><Author>Felice</Author><Year>2009</Year><RecNum>841</RecNum><DisplayText><style face="superscript">101</style></DisplayText><record><rec-number>841</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1600181842">841</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Felice, B.</author><author>Cattoglio, C.</author><author>Cittaro, D.</author><author>Testa, A.</author><author>Miccio, A.</author><author>Ferrari, G.</author><author>Luzi, L.</author><author>Recchia, A.</author><author>Mavilio, F.</author></authors></contributors><auth-address>IFOM, FIRC Institute of Molecular Oncology Foundation, Milan, Italy.</auth-address><titles><title>Transcription factor binding sites are genetic determinants of retroviral integration in the human genome</title><secondary-title>PLoS One</secondary-title></titles><periodical><full-title>PLoS One</full-title></periodical><pages>e4571</pages><volume>4</volume><number>2</number><edition>2009/02/25</edition><keywords><keyword>Binding Sites</keyword><keyword>Computational Biology/methods</keyword><keyword>Gammaretrovirus/physiology</keyword><keyword>*Genome, Human</keyword><keyword>Humans</keyword><keyword>Integrases/genetics</keyword><keyword>Lentivirus/physiology</keyword><keyword>Mutation</keyword><keyword>Retroviridae/*physiology</keyword><keyword>Terminal Repeat Sequences/genetics</keyword><keyword>Transcription Factors/*metabolism</keyword><keyword>*Virus Integration</keyword></keywords><dates><year>2009</year></dates><isbn>1932-6203 (Electronic)
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ADDIN EN.CITE.DATA 104. Semi-random vector integration could potentially induce changes in gene structure or expression that may provide a selective clonal growth advantage or result in uncontrolled proliferation ADDIN EN.CITE <EndNote><Cite><Author>Bushman</Author><Year>2020</Year><RecNum>701</RecNum><DisplayText><style face="superscript">105</style></DisplayText><record><rec-number>701</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">701</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bushman, F. D.</author></authors></contributors><auth-address>Department of Microbiology, University of Pennsylvania Perelman School of Medicine, 3610 Hamilton Walk, Philadelphia, PA 19104-6076, USA. Electronic address: bushman@mail.med.upenn.edu.</auth-address><titles><title>Retroviral Insertional Mutagenesis in Humans: Evidence for Four Genetic Mechanisms Promoting Expansion of Cell Clones</title><secondary-title>Molecular therapy : the journal of the American Society of Gene Therapy</secondary-title><alt-title>Mol Ther</alt-title></titles><alt-periodical><full-title>Mol Ther</full-title></alt-periodical><edition>2020/01/18</edition><dates><year>2020</year><pub-dates><date>Jan 7</date></pub-dates></dates><isbn>1525-0024 (Electronic)
1525-0016 (Linking)</isbn><accession-num>31951833</accession-num><work-type>Review</work-type><urls><related-urls><url>. The first vector integration studies in patients with ADA-SCID treated with gammaretroviral vectors showed the existence of insertion sites shared among multiple haematopoietic lineages, indicating bona fide engrafted, transduced HSPCsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWFzY288L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 108,109. Linear-amplification mediated PCR (LAM-PCR) amplification and other methods that avoid restriction enzymes ADDIN EN.CITE <EndNote><Cite><Author>Bushman</Author><Year>2020</Year><RecNum>701</RecNum><DisplayText><style face="superscript">105</style></DisplayText><record><rec-number>701</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">701</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bushman, F. D.</author></authors></contributors><auth-address>Department of Microbiology, University of Pennsylvania Perelman School of Medicine, 3610 Hamilton Walk, Philadelphia, PA 19104-6076, USA. Electronic address: bushman@mail.med.upenn.edu.</auth-address><titles><title>Retroviral Insertional Mutagenesis in Humans: Evidence for Four Genetic Mechanisms Promoting Expansion of Cell Clones</title><secondary-title>Molecular therapy : the journal of the American Society of Gene Therapy</secondary-title><alt-title>Mol Ther</alt-title></titles><alt-periodical><full-title>Mol Ther</full-title></alt-periodical><edition>2020/01/18</edition><dates><year>2020</year><pub-dates><date>Jan 7</date></pub-dates></dates><isbn>1525-0024 (Electronic)
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ADDIN EN.CITE.DATA 15,108,112. However, continuous insertion profiling was not able to detect the onset of leukaemia in patients who went on to develop the disease following HSPC gene therapy until clinical symptoms had become apparent ADDIN EN.CITE <EndNote><Cite><Author>Biasco</Author><Year>2018</Year><RecNum>735</RecNum><DisplayText><style face="superscript">111</style></DisplayText><record><rec-number>735</rec-number><foreign-keys><key app="EN" db-id="2r9srez2ls20dpet0s6p0sddepwdxd592vea" timestamp="0">735</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Biasco, L.</author><author>Rothe, M.</author><author>Buning, H.</author><author>Schambach, A.</author></authors></contributors><auth-address>San Raffaele Telethon Institute for Gene Therapy, Milan, Italy.
Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Department of Pediatric Oncology, Harvard Medical School, Boston, MA, USA.
Institute of Child Health, University College London, London, UK.
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.</auth-address><titles><title>Analyzing the Genotoxicity of Retroviral Vectors in Hematopoietic Cell Gene Therapy</title><secondary-title>Molecular therapy. Methods & clinical development</secondary-title><alt-title>Mol Ther Methods Clin Dev</alt-title></titles><pages>21-30</pages><volume>8</volume><edition>2017/11/22</edition><dates><year>2018</year><pub-dates><date>Mar 16</date></pub-dates></dates><isbn>2329-0501 (Print)
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ADDIN EN.CITE.DATA 113. The patient was found to have a dominant clone harbouring an integration in the HMGA2 gene, causing deregulation of HMGA2 expression that was not associated with adverse effects. The risk of genotoxicity for lentiviral insertions using a safe vector backbone and an adequate dose of HSC is therefore predicted to be lowPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWZmaTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 68,114. Recent studies monitoring the kinetics of blood cell production from individual HSPCs suggest that distinct subtypes contribute to early and late post-transplantation phases differently. In particular, these studies showed that multi-potent progenitors activate soon after transplant and dominate initial haematopoietic output, whereas long-term repopulating HSPCs become predominant 1–2 years after transplantation, once haematopoiesis reaches a steady statePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWFzY288L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 116,118. However, it should be noted that these studies are based on data derived from gene therapy trials for PIDs and could be biased towards reconstitution of the lymphoid compartment. In cases where gene editing is used in HSPC gene therapy, studying the safety and dynamics of the corrected cell population could prove challenging owing to the lack of a distinctive element identifying each clone, especially when high fidelity homology repair (HDR) is performed. Clonality studies may be useful in the case of non-homologous end joining (NHEJ) editing, since the DNA breaks produces insertions and deletions (indels) of different length that can be sequenced by next generation sequencing techniques. [H1] Applications for HSPC gene therapy [H2] Primary immunodeficiencies Primary immunodeficiencies (PIDs) are a heterogeneous group of rare heritable disorders that result in an underdeveloped and/or functionally compromised immune system ADDIN EN.CITE <EndNote><Cite><Author>Ochs</Author><Year>2014</Year><RecNum>703</RecNum><DisplayText><style face="superscript">119</style></DisplayText><record><rec-number>703</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">703</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ochs, H. D.</author><author>Hagin, D.</author></authors></contributors><auth-address>Seattle Children's Research Institute, University of Washington, Seattle, Washington. Electronic address: allgau@u.washington.edu.
Seattle Children's Research Institute, University of Washington, Seattle, Washington.</auth-address><titles><title>Primary immunodeficiency disorders: general classification, new molecular insights, and practical approach to diagnosis and treatment</title><secondary-title>Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology</secondary-title><alt-title>Ann Allergy Asthma Immunol</alt-title></titles><pages>489-95</pages><volume>112</volume><number>6</number><edition>2014/05/28</edition><keywords><keyword>Antibodies/immunology</keyword><keyword>B-Lymphocytes/immunology</keyword><keyword>*Hereditary Autoinflammatory Diseases/diagnosis/genetics/immunology</keyword><keyword>Humans</keyword><keyword>Immunologic Deficiency Syndromes/*classification/diagnosis/genetics</keyword><keyword>Neutrophils/immunology</keyword><keyword>T-Lymphocytes/immunology</keyword></keywords><dates><year>2014</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1534-4436 (Electronic)
1081-1206 (Linking)</isbn><accession-num>24860921</accession-num><work-type>Review</work-type><urls><related-urls><url>. Patients with severe PIDs such as forms of severe combined immunodeficiency (SCID), combined immunodeficiency (CID) or severe myeloid cell disorders experience increase morbidity and mortality and display diverse clinical phenotypesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW5neWU8L0F1dGhvcj48WWVhcj4yMDIwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 120. HSCT using HSPCs from an HLA-matched donor can confer a lifelong ‘cure’, with a success rate of more than 90%PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZW5uZXJ5PC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48
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ADDIN EN.CITE.DATA 121,122, ADDIN EN.CITE <EndNote><Cite><Author>Castagnoli</Author><Year>2019</Year><RecNum>707</RecNum><DisplayText><style face="superscript">123</style></DisplayText><record><rec-number>707</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">707</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Castagnoli, R.</author><author>Delmonte, O. M.</author><author>Calzoni, E.</author><author>Notarangelo, L. D.</author></authors></contributors><auth-address>Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
Department of Pediatrics, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
Department of Molecular and Translational Medicine, A. Nocivelli Institute for Molecular Medicine, University of Brescia, Brescia, Italy.</auth-address><titles><title>Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Diseases: Current Status and Future Perspectives</title><secondary-title>Frontiers in pediatrics</secondary-title><alt-title>Front Pediatr</alt-title></titles><pages>295</pages><volume>7</volume><edition>2019/08/24</edition><dates><year>2019</year></dates><isbn>2296-2360 (Print)
2296-2360 (Linking)</isbn><accession-num>31440487</accession-num><work-type>Review</work-type><urls><related-urls><url>; however, the limited availability of HLA-matched donors, particularly in certain populations and non-western geographies, results in the necessity to use unmatched donors, which increases treatment-related risk due to GVHD, toxicity and infections, the risks of which depend on age, co-morbidities and genotype ADDIN EN.CITE <EndNote><Cite><Author>Castagnoli</Author><Year>2019</Year><RecNum>707</RecNum><DisplayText><style face="superscript">123</style></DisplayText><record><rec-number>707</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">707</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Castagnoli, R.</author><author>Delmonte, O. M.</author><author>Calzoni, E.</author><author>Notarangelo, L. D.</author></authors></contributors><auth-address>Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
Department of Pediatrics, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
Department of Molecular and Translational Medicine, A. Nocivelli Institute for Molecular Medicine, University of Brescia, Brescia, Italy.</auth-address><titles><title>Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Diseases: Current Status and Future Perspectives</title><secondary-title>Frontiers in pediatrics</secondary-title><alt-title>Front Pediatr</alt-title></titles><pages>295</pages><volume>7</volume><edition>2019/08/24</edition><dates><year>2019</year></dates><isbn>2296-2360 (Print)
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ADDIN EN.CITE.DATA 120 As a result, these conditions are associated with a high mortality in early life owing to severe infection. The success of HSCT gene therapy in treating many of these conditions is likely due to both a growth and survival advantage for gene-corrected cells and the inability of patients with SCID to reject allogeneic grafts. Because of these factors, successful engraftment of graft lymphocytes can occur without the need for cytoreductive conditioning ADDIN EN.CITE <EndNote><Cite><Author>Buckley</Author><Year>2004</Year><RecNum>710</RecNum><DisplayText><style face="superscript">124</style></DisplayText><record><rec-number>710</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">710</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Buckley, R. H.</author></authors></contributors><auth-address>Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. BUCKL003@mc.duke.edu</auth-address><titles><title>Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution</title><secondary-title>Annual review of immunology</secondary-title><alt-title>Annu Rev Immunol</alt-title></titles><pages>625-55</pages><volume>22</volume><edition>2004/03/23</edition><keywords><keyword>*Bone Marrow Transplantation</keyword><keyword>Child</keyword><keyword>Chromosome Aberrations</keyword><keyword>Clinical Trials as Topic</keyword><keyword>*Genetic Therapy</keyword><keyword>Humans</keyword><keyword>Immunity, Cellular</keyword><keyword>Infant</keyword><keyword>Severe Combined Immunodeficiency/*genetics/*therapy</keyword></keywords><dates><year>2004</year></dates><isbn>0732-0582 (Print)
0732-0582 (Linking)</isbn><accession-num>15032591</accession-num><work-type>Review</work-type><urls><related-urls><url>. The capacity for PID patients to accommodate donor lymphocytes, predominantly T cells, is unsurprising considering patients with PID can acquire somatic mosaicism and a milder or ‘atypical’ phenotype through spontaneous genetic reversions and second-site mutations ADDIN EN.CITE <EndNote><Cite><Author>Wada</Author><Year>2008</Year><RecNum>800</RecNum><DisplayText><style face="superscript">125</style></DisplayText><record><rec-number>800</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1587045787">800</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wada, T.</author><author>Candotti, F.</author></authors></contributors><auth-address>Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.</auth-address><titles><title>Somatic mosaicism in primary immune deficiencies</title><secondary-title>Curr Opin Allergy Clin Immunol</secondary-title><alt-title>Current opinion in allergy and clinical immunology</alt-title></titles><pages>510-4</pages><volume>8</volume><number>6</number><keywords><keyword>Animals</keyword><keyword>Cell Lineage/genetics</keyword><keyword>Chromosomes, Human, Pair 12</keyword><keyword>Codon, Nonsense</keyword><keyword>DNA Repair/immunology</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Immunologic Deficiency Syndromes/blood/*genetics/pathology</keyword><keyword>Infant, Newborn</keyword><keyword>*Mosaicism</keyword><keyword>Risk Factors</keyword><keyword>Wiskott-Aldrich Syndrome/blood/*genetics/pathology</keyword></keywords><dates><year>2008</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1473-6322 (Electronic)
1473-6322 (Linking)</isbn><accession-num>18978464</accession-num><urls><related-urls><url>. SCID-X1 is caused by a deficiency of the cytokine receptor common subunit γ (also known as IL-2RG) — a critical component of multiple cytokine receptors including the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors — which results in the absence of T cells and NK cells, and the presence of functionally deficient B cells ADDIN EN.CITE <EndNote><Cite><Author>Fischer</Author><Year>2020</Year><RecNum>711</RecNum><DisplayText><style face="superscript">126</style></DisplayText><record><rec-number>711</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">711</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fischer, A.</author><author>Hacein-Bey-Abina, S.</author></authors></contributors><auth-address>Imagine Institute, Paris, France.
Immunology and Pediatric Hematology Department, Assistance Publique-Hopitaux de Paris, Paris, France.
Institut National de la Sante et de la Recherche Medicale UMR 1163, Paris, France.
College de France, Paris, France.
Unite de Technologies Chimiques et Biologiques pour la Sante, UMR8258 Centre National de la Recherche Scientifique - U1267 Institut National de la Sante et de la Recherche Medicale, Faculte de Pharmacie de Paris, Universite Paris Descartes, Paris, France.
Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Hopital Kremlin-Bicetre, Assistance Publique-Hopitaux de Paris, Le Kremlin Bicetre, France.</auth-address><titles><title>Gene therapy for severe combined immunodeficiencies and beyond</title><secondary-title>The Journal of experimental medicine</secondary-title><alt-title>J Exp Med</alt-title></titles><volume>217</volume><number>2</number><edition>2019/12/12</edition><dates><year>2020</year><pub-dates><date>Jan 6</date></pub-dates></dates><isbn>1540-9538 (Electronic)
0022-1007 (Linking)</isbn><accession-num>31826240</accession-num><urls><related-urls><url>. Early trials conducted using conventional gammaretroviral vectors with intact LTRs demonstrated rapid reconstitution of T-cell immunity as a result of gene-corrected HSPC-mediated initiation of thymopoiesis in 17 of 20 patients treatedPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWNlaW4tQmV5LUFiaW5hPC9BdXRob3I+PFllYXI+MjAx
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ADDIN EN.CITE.DATA 34,87 (Fig. 2). Humoral immunity was only partially restored, as the absence of cytoreductive conditioning and sustained HSC engraftment in these studies meant the resident B lymphocyte lineages remained uncorrected. Somewhat surprisingly, active thymopoiesis seemed to be maintained for many years after treatmentPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GaXNjaGVyPC9BdXRob3I+PFllYXI+MjAyMDwvWWVhcj48
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ADDIN EN.CITE.DATA 15. The occurrence of similar pathologies in other trials not related to SCID-X1PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmF1bjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmF1bjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 108 using gammaretroviral vectors indicated the gene transfer technology specifically was inducing leukaemia. To address these issues, alternative vector platforms based on LTR enhancer-deleted gammaretrovirusesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWNlaW4tQmV5LUFiaW5hPC9BdXRob3I+PFllYXI+MjAx
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ADDIN EN.CITE.DATA 129. This observation suggests that even at late stages, thymopoiesis is a retrievable developmental programme as long as there is a supply of gene-corrected T cell progenitors.[H3] Adenosine deaminase-deficient severe combined immunodeficiency ADA-SCID is an autosomal recessive metabolic disease caused by mutations in the gene encoding adenosine deaminase (ADA), which result in the accumulation of toxic metabolites such as deoxyadenosine that compromise lymphoid development. Enzyme replacement therapy through weekly administration of PEGylated bovine or recombinant adenosine deaminase can ameliorate the build-up of these metabolites in the blood and allows variable restoration of lymphopoiesis, albeit at a high financial cost ADDIN EN.CITE <EndNote><Cite><Author>Kohn</Author><Year>2019</Year><RecNum>695</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>695</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">695</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kohn, D. B.</author></authors></contributors><auth-address>Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, David Geffen School of Medicine, USA; Department of Pediatrics, University of California, Los Angeles, David Geffen School of Medicine, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, David Geffen School of Medicine, USA. Electronic address: dkohn1@mednet.ucla.ediu.</auth-address><titles><title>Gene therapy for blood diseases</title><secondary-title>Current opinion in biotechnology</secondary-title><alt-title>Curr Opin Biotechnol</alt-title></titles><pages>39-45</pages><volume>60</volume><edition>2019/01/02</edition><dates><year>2019</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1879-0429 (Electronic)
0958-1669 (Linking)</isbn><accession-num>30599357</accession-num><work-type>Review</work-type><urls><related-urls><url>. Early attempts at gene therapy targeting residual mature T lymphocytes had minimal clinical benefit as patients were maintained on enzyme replacement therapy (ERT)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3JkaWdub248L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFy
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ADDIN EN.CITE.DATA 132 (Fig. 2). Strimvelis, a gene therapy based on the introduction of ADA genes into HSCs using a gammaretroviral vector, was the first ex vivo gene therapy to be licensed in 2016 ADDIN EN.CITE <EndNote><Cite><Author>Aiuti</Author><Year>2017</Year><RecNum>676</RecNum><DisplayText><style face="superscript">133</style></DisplayText><record><rec-number>676</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">676</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aiuti, A.</author><author>Roncarolo, M. G.</author><author>Naldini, L.</author></authors></contributors><auth-address>San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.
Vita Salute San Raffaele University, Milan, Italy.</auth-address><titles><title>Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products</title><secondary-title>EMBO molecular medicine</secondary-title><alt-title>EMBO Mol Med</alt-title></titles><alt-periodical><full-title>EMBO Mol Med</full-title></alt-periodical><pages>737-740</pages><volume>9</volume><number>6</number><edition>2017/04/12</edition><keywords><keyword>Adenosine Deaminase/*deficiency/genetics</keyword><keyword>Agammaglobulinemia/genetics/*therapy</keyword><keyword>Child</keyword><keyword>Europe</keyword><keyword>*Genetic Therapy</keyword><keyword>Genetic Vectors/therapeutic use</keyword><keyword>Hematopoietic Stem Cell Transplantation</keyword><keyword>Humans</keyword><keyword>Severe Combined Immunodeficiency/genetics/*therapy</keyword><keyword>Transplantation, Autologous</keyword></keywords><dates><year>2017</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1757-4684 (Electronic)
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ADDIN EN.CITE.DATA 137.[H3] Other primary immunodeficiencies Many other PIDs that are currently treatable using allogeneic HSCT are viable targets for an autologous gene therapy approach. Wiskott–Aldrich syndrome is a complex, multi-lineage PID caused by mutations in the WAS gene that result in haematopoietic cell cytoskeletal dysfunction, and is further complicated by thrombocytopenia [G] ADDIN EN.CITE <EndNote><Cite><Author>Thrasher</Author><Year>2010</Year><RecNum>721</RecNum><DisplayText><style face="superscript">138</style></DisplayText><record><rec-number>721</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">721</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thrasher, A. J.</author><author>Burns, S. O.</author></authors></contributors><auth-address>Molecular Immunology Unit and Centre for Immunodeficiency, University College London Institute of Child Health, London, UK.</auth-address><titles><title>WASP: a key immunological multitasker</title><secondary-title>Nature reviews. Immunology</secondary-title><alt-title>Nat Rev Immunol</alt-title></titles><pages>182-92</pages><volume>10</volume><number>3</number><edition>2010/02/26</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Immunity, Innate/immunology</keyword><keyword>Neutropenia/genetics/*immunology</keyword><keyword>Wiskott-Aldrich Syndrome/genetics/*immunology</keyword><keyword>Wiskott-Aldrich Syndrome Protein/deficiency/genetics/*immunology</keyword></keywords><dates><year>2010</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1474-1741 (Electronic)
1474-1733 (Linking)</isbn><accession-num>20182458</accession-num><work-type>Research Support, Non-U.S. Gov't
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ADDIN EN.CITE.DATA 141 and RAG ADDIN EN.CITE <EndNote><Cite><Author>Kohn</Author><Year>2019</Year><RecNum>695</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>695</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">695</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kohn, D. B.</author></authors></contributors><auth-address>Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, David Geffen School of Medicine, USA; Department of Pediatrics, University of California, Los Angeles, David Geffen School of Medicine, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, David Geffen School of Medicine, USA. Electronic address: dkohn1@mednet.ucla.ediu.</auth-address><titles><title>Gene therapy for blood diseases</title><secondary-title>Current opinion in biotechnology</secondary-title><alt-title>Curr Opin Biotechnol</alt-title></titles><pages>39-45</pages><volume>60</volume><edition>2019/01/02</edition><dates><year>2019</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1879-0429 (Electronic)
0958-1669 (Linking)</isbn><accession-num>30599357</accession-num><work-type>Review</work-type><urls><related-urls><url>
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ADDIN EN.CITE.DATA 142 (Table 1).[H2] Erythrocyte disordersGenetic diseases that affect red blood cells and are treatable using HSPC gene therapy include β-thalassaemia, SCD and pyruvate kinase deficiency (PKD). In SCD and β-thalassaemia, both of which are caused by mutations in HBB — the gene that encodes β-globin — gene therapy is particularly challenging because the inclusion of large-scale HBB genomic sequences and locus control region elements is a limiting factor in the design and manufacture of high-titre vectorsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JnYW48L0F1dGhvcj48WWVhcj4yMDIwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 143. From a safety point of view, the use of erythroid-specific regulatory sequences restricts the genotoxic risk of gene transactivation to erythroid precursors committed to enucleation and with a limited half-life.[H3] β-thalassaemiaIn β-thalassaemia, mutations in HBB — the gene encoding the β-globin chain of haemoglobin — result in an imbalance between α-globin and β-globin chains that is toxic to erythroid precursors. β-thalassaemia major is a particularly severe form of β-thalassaemia associated with chronic and severe anaemia, caused by homozygous inactivating mutations in the β-globin gene (represented as βo/βo) and currently requires lifelong monthly blood transfusions and iron chelation treatment [G]. Allogeneic HSCT has been used to cure β-thalassaemia, but is only available to the minority of patients who have a compatible donorPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmdlbHVjY2k8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy
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ADDIN EN.CITE.DATA 24. Clinical outcome was dependent on genotype, with 80% of patients with non-β0/β0 genotypes and 38% with β0/β0 genotypes achieving transfusion independence at the 2 year follow-up. The remaining patients exhibited varying levels of transfusion reduction. On the basis of these results, in 2019 the EMA gave conditional marketing authorization to ZyntegloTM for patients with TDT with non-β0/β0 genotypes [Au:OK?]. Optimization of the transduction protocol led to the start of two phase III clinical trials that are current ongoing (Table 1, NCT02906202 and NCT03207009). In the TIGET-BTHAL clinical trial (Table 1, NCT02453477), nine patients with β0/β0 genotypes, including six minors, were treated using intra-bone administration of GLOBE lentiviral vector-transduced HSPCs. In the 1 year follow-up, the primary endpoints of transfusion reduction and safety were achieved in all patients, with four patients achieving transfusion independence. Patients with clinical benefit showed robust and stable engraftment of genetically-modified cells in all lineages, including bone marrow erythroid cellsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJrdGVsPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48
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ADDIN EN.CITE.DATA 83 and in thalassaemic mice with defective HSPC function in the latter caused by altered niche–HSPC crosstalk ADDIN EN.CITE <EndNote><Cite><Author>Aprile</Author><Year>2020</Year><RecNum>811</RecNum><DisplayText><style face="superscript">84</style></DisplayText><record><rec-number>811</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1588696701">811</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aprile, A.</author><author>Gulino, A.</author><author>Storto, M.</author><author>Villa, I.</author><author>Beretta, S.</author><author>Merelli, I.</author><author>Rubinacci, A.</author><author>Ponzoni, M.</author><author>Marktel, S.</author><author>Tripodo, C.</author><author>Lidonnici, M. R.</author><author>Ferrari, G.</author></authors></contributors><auth-address>IRCCS San Raffaele Scientific Institute, Milan, Italy.
University of Palermo.
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Milano, Italy.
San Raffaele Scientific Institute, Milano, Italy.
IRCCS San Raffaele Scientific Institute, Italy.
Ospedale S. Raffaele H. Scientific Institute, Milan, Italy.
San Raffaele Scientific Institute, Milan, Italy.
University of Palermo, Palermo, Italy.
1San Raffaele-Telethon Institute for Gene Therapy (TIGET), Milan, Italy.
VITA- San Raffaele Scientific Institute, Milan, Italy.</auth-address><titles><title>Hematopoietic stem cell function in beta-thalassemia is impaired and is rescued by targeting the bone marrow niche</title><secondary-title>Blood</secondary-title><alt-title>Blood</alt-title></titles><periodical><full-title>Blood</full-title></periodical><alt-periodical><full-title>Blood</full-title></alt-periodical><dates><year>2020</year><pub-dates><date>Apr 28</date></pub-dates></dates><isbn>1528-0020 (Electronic)
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ADDIN EN.CITE.DATA 146,147. SCD is caused by a single-nucleotide mutation in HBB, resulting in the production of the toxic haemoglobin variant HbS, which polymerizes into long fibres that deform red blood cells into a sickled shape. Gene therapy strategies for SCD either use transgenes encoding foetal ??globin or β-globins with anti-sickling activity such as βT87Q, βAS3; reactivate HbF production by generating HPFH mutations, or suppress the biological action of BCL11A, a major repressor of ??globin genesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5rYXJhbjwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+
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ADDIN EN.CITE.DATA 150. Using Plerixafor-mobilized HSPCs instead of bone marrow-derived HSPCs and increasing the transduction level with an culture optimized protocol ADDIN EN.CITE <EndNote><Cite><Author>Kanter J.</Author><Year>2019</Year><RecNum>757</RecNum><DisplayText><style face="superscript">151</style></DisplayText><record><rec-number>757</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">757</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kanter J., Tisdale FJ., Mapara MY., Kwiatkowski JL., Krishnamurti L., Manfred Schmidt M., Miller AL., Pierciey FJ, Wenmei Huang W., Ribeil JA, Thompson AA, Walters MC.</author></authors></contributors><titles><title>Resolution of Sickle Cell Disease Manifestations in Patients Treated with Lentiglobin Gene Therapy: Updated Results from the Phase 1/2 Hgb-206 Group C Study</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>990</pages><volume>134 (Supplement_1)</volume><dates><year>2019</year></dates><urls></urls><electronic-resource-num> has since improved the clinical outcome, with recent results showing sustained expression of transgenic anti-sickling β-globin and decreased SCD manifestations ADDIN EN.CITE <EndNote><Cite><Author>Tisdale</Author><Year>2020</Year><RecNum>631</RecNum><DisplayText><style face="superscript">152</style></DisplayText><record><rec-number>631</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">631</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tisdale, F.J.</author><author>Kanter, J.</author><author>Mapara, M.Y.</author><author>Kwiatkowski, J.L.</author><author>Krishnamurti, L.</author><author>Schmidt, M.</author><author>Miller, A.L.</author><author>Pierciey, F.J.</author><author>Huang, W.</author><author>Ribeil, J.A.</author><author>Thompson, A.A.</author><author>Walters, M.C.</author></authors></contributors><titles><title>Resolution of sickle cell disease (SCD) manifestations in patients treated with lentiglobin gene therapy: Updated results from the phase 1/2 HGB-206 group C study.</title><secondary-title>Molecular Therapy</secondary-title></titles><pages>553</pages><volume>28</volume><number>4S1</number><num-vols>Supplement 1</num-vols><dates><year>2020</year><pub-dates><date>2020</date></pub-dates></dates><urls></urls></record></Cite></EndNote>152. Two further phase I and II lentiviral vector-based clinical trials for SCD are currently ongoing; in one trial, the patients are subject to reduced-intensity conditioning and transplanted with HSC expressing the ?-globin gene ADDIN EN.CITE <EndNote><Cite><Author>Malik P.</Author><Year>2018</Year><RecNum>758</RecNum><DisplayText><style face="superscript">153</style></DisplayText><record><rec-number>758</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">758</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Malik P., Grimley M., Quinn CT., Shova A., Courtney L., Lutzko C., Kalfa TA., Niss O., Mehta PA., Chandra S., Grassman E., Van der Loo JCM., Witting S., Nordling D., Shreshta A., Felker S., Terrell C., Reeves L., Pillis D., Anastacia L., Bushman FD, Knight-Madden J., Kalinyak K., Davies SM., Asnani M., </author></authors></contributors><titles><title>Gene Therapy for Sickle Cell Anemia Using a Modified Gamma Globin Lentivirus Vector and Reduced Intensity Conditioning Transplant Shows Promising Correction of the Disease Phenotype </title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>1021</pages><volume>132 (Supplement_1)</volume><dates><year>2018</year></dates><urls></urls><electronic-resource-num>
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ADDIN EN.CITE.DATA 154. A phase I clinical trial using this technology started in 2018 for patients with SCD (Table 1), with promising initial results showing HbF reactivation ADDIN EN.CITE <EndNote><Cite><Author>Esrick EB</Author><Year>2019</Year><RecNum>759</RecNum><DisplayText><style face="superscript">155</style></DisplayText><record><rec-number>759</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">759</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author> Esrick EB, Achebe M., Armant M., Bartolucci P., Ciuculescu MF.,Daley H.,Dansereau C., Di Caprio G., Goncalves B., Hebert N., Heeney MM., Higgins JM., Lehmann L., Manis JP., Negre O., Nikiforow S., Schonbrun E., Wood DK., Williams, DA.</author></authors></contributors><titles><title>Validation of BCL11A As Therapeutic Target in Sickle Cell Disease: Results from the Adult Cohort of a Pilot/Feasibility Gene Therapy Trial Inducing Sustained Expression of Fetal Hemoglobin Using Post-Transcriptional Gene Silencing </title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>LBA-5</pages><volume>134 (Supplement_2)</volume><dates><year>2019</year></dates><urls></urls><electronic-resource-num>
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ADDIN EN.CITE.DATA 156, and a phase I/II clinical trial has recently been approved.[H2] Bone marrow failure syndromesFanconi anaemia is a congenital, autosomal recessive DNA repair disorder associated with developmental abnormalities, bone marrow failure and a predisposition to cancers. A number of genes involved in DNA replication and repair have been implicated in Fanconi anaemia, including FANCA and FANCB. In a recent clinical study, patients with Fanconi anaemia caused by FANCA mutations received lentivirus-mediated HSPC gene therapy aiming to transfer an intact copy of the FANCA genePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaW88L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 158. These issues could be addressed using HSPC gene therapy as HSPCs and blood cells of the myeloid lineage are able to penetrate into the CNS and replace the resident populations of tissue macrophages and microglia-like cells ADDIN EN.CITE <EndNote><Cite><Author>Orchard</Author><Year>2011</Year><RecNum>724</RecNum><DisplayText><style face="superscript">159</style></DisplayText><record><rec-number>724</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">724</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Orchard, P. J.</author><author>Wagner, J. E.</author></authors></contributors><auth-address>Department of Pediatrics and the Bone and Marrow Transplant Program, University of Minnesota Medical School, Minneapolis, USA.</auth-address><titles><title>Leukodystrophy and gene therapy with a dimmer switch</title><secondary-title>The New England journal of medicine</secondary-title><alt-title>N Engl J Med</alt-title></titles><pages>572-3</pages><volume>364</volume><number>6</number><edition>2011/02/11</edition><keywords><keyword>Galactosylceramidase/*genetics/metabolism</keyword><keyword>*Gene Expression Regulation</keyword><keyword>*Genetic Therapy</keyword><keyword>Hematopoietic Stem Cells/metabolism</keyword><keyword>Humans</keyword><keyword>Leukodystrophy, Globoid Cell/genetics/*therapy</keyword><keyword>*MicroRNAs</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb 10</date></pub-dates></dates><isbn>1533-4406 (Electronic)
0028-4793 (Linking)</isbn><accession-num>21306246</accession-num><urls><related-urls><url>, ADDIN EN.CITE <EndNote><Cite><Author>Krivit</Author><Year>1987</Year><RecNum>725</RecNum><DisplayText><style face="superscript">160</style></DisplayText><record><rec-number>725</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">725</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Krivit, W.</author><author>Whitley, C. B.</author></authors></contributors><titles><title>Bone marrow transplantation for genetic diseases</title><secondary-title>The New England journal of medicine</secondary-title><alt-title>N Engl J Med</alt-title></titles><pages>1085-7</pages><volume>316</volume><number>17</number><edition>1987/04/23</edition><keywords><keyword>Adolescent</keyword><keyword>*Bone Marrow Transplantation</keyword><keyword>Child</keyword><keyword>Genetic Diseases, Inborn/*therapy</keyword><keyword>Humans</keyword><keyword>Metabolism, Inborn Errors/therapy</keyword><keyword>Thalassemia/therapy</keyword></keywords><dates><year>1987</year><pub-dates><date>Apr 23</date></pub-dates></dates><isbn>0028-4793 (Print)
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ADDIN EN.CITE.DATA 158. This may be because of insufficient cross-correction of the metabolic defect in non-hematopoietic cells in the short time available to control rapid disease progression. Genetic modification of HSPCs designed to overexpress therapeutic proteins could therefore increase therapeutic protein levels in the blood and multiple tissues including the CNS and bone and provide enhanced cross-correction capacity, compensating for the presence of residual, uncorrected host cells (Fig. 6) Individual neurometabolic disorders are discussed below. [H3] X-linked adrenoleukodystrophy X-linked adrenoleukodystrophy (X-ALD) is a severe demyelinating disease caused by defects in the degradation of very long-chain fatty acids induced by a deficiency in ALD protein (encoded by ABCD1). The cerebral form of X-ALD is characterized by learning and behavioral problems starting at a median age of 7 years, followed by rapid neurological deterioration. Brain inflammation with infiltration of monocytes and microglia loss are hallmarks of the disease. The beneficial effects of transplantation are thought to be mediated by donor replacement of defective myeloid cellsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FaWNobGVyPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
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ADDIN EN.CITE.DATA 26. Peroxisomal enzymes are not secreted and the mechanism of disease amelioration for peroxisomal storage diseases is still not well understood, although it has been hypothesized that corrected cells can restore the metabolism of non-functional neuronal cells through direct intercellular contactPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW1hZGE8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 166. [H3] Metachromatic leukodystrophyMetachromatic leukodystrophy (MLD) is a severe lysosomal storage disorder caused by mutations in ARSA, a gene encoding arylsulfatase A (ARSA). ARSA deficiency results in the accumulation of sulfatides in the CNS and peripheral nervous system, leading to progressive demyelination and neurodegeneration. The first clinical trial based on HSPCs transduced with a lentiviral vector encoding ARSA showed safety and efficacy in eight out of nine MLD patients treated at a pre-symptomatic or very early-symptomatic stagePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWZmaTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ZT4A
ADDIN EN.CITE.DATA 68. Treatment restored ARSA activity in patient circulating haematopoietic cells and in the cerebrospinal fluid to normal or above-normal levels — indicating local production by corrected HSPC-derived cells — and either prevented disease onset or progression. In contrast to untreated patients and their siblings, most treated patients displayed continuous motor and cognitive developmentPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXNzYTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 77 at a median follow up of 3 years; these results have since been confirmed in a larger cohort of patients up to 7.5 years of follow up ADDIN EN.CITE <EndNote><Cite><Author>Fumagalli</Author><Year>2019</Year><RecNum>828</RecNum><DisplayText><style face="superscript">167</style></DisplayText><record><rec-number>828</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1595240054">828</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fumagalli, F.</author><author>Calbi, V.</author><author>Sessa, M.</author><author>Zambon, A.</author><author>Baldoli, C.</author><author>Cugnata, F.</author><author>Rancoita, P.V.M.</author><author>Acquati, S.</author><author>Miglietta, S.</author><author>Magni, S.</author><author>Recupero, S.</author><author>Ferrua, F.</author><author>Barzaghi, F.</author><author>Cicalese, M. P.</author><author>Migliavacca, M.</author><author>Tucci, F.</author><author>Gallo, V.</author><author>Ciotti, F.</author><author>Fraschini, M.</author><author>Sarzana, M.</author><author>Silvani, P.</author><author>Spiga, I.</author><author>Ferrari, M.</author><author>Facchini, M.</author><author>Locatelli, S.</author><author>Antomioli, G.</author><author>Zancan, S.</author><author>Calabria, A.</author><author>Montini, E.</author><author>Farinelli, G.</author><author>Morena, F.</author><author>Segovia, J. C.</author><author>Scwab, L.C.</author><author>Downey, G</author><author>Gabaldo, M.</author><author>Martino, S.</author><author>Di Serio, C.</author><author>Ciceri, F.</author><author>Comi, G.</author><author>Natali-Sora, M.</author><author>Bernardo, M. E.</author><author>Naldini, L.</author><author>Biffi, A.</author><author>Aiuti, A.</author></authors></contributors><titles><title>Lentiviral (LV) hematopoietic stem cell gene therapy (HSC-GT) for metachromatic leukodystrophy (MLD).</title><secondary-title>Journal of Inherited Metabolic Disease</secondary-title></titles><pages>7</pages><volume>42</volume><num-vols>Suppl.1</num-vols><dates><year>2019</year></dates><urls></urls></record></Cite></EndNote>167. Marketing authorization for this gene therapy based medicinal product (Libmeldy) is currently under evaluation in the EU. This study represents a key proof of principle indicating that HSPC gene therapy could be used as a therapeutic strategy for lysosomal storage disorders. [H3] Mucopolysaccharidosis MPS is a group of rare heterogenous diseases caused by deficiencies in enzymes involved in the breakdown of glycosaminoglycans (GAG). These diseases manifest with somatic and neurological symptoms, depending on the type of accumulating GAGPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QbGF0dDwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 168. People with the severe form of MPS type I (Hurler syndrome), which is caused by a deficiency in the enzyme iduronidase, usually develop skeletal abnormalities, hepatosplenomegaly, specific facial features, visual, heart and respiratory problems, and developmental delay, becoming severely intellectually disabled. The physical features of MPS type III patients (Sanfilippo syndrome) are less pronounced than those of with MPSI and these children develop neurodegeneration with impaired cognition and behavioral and sleeping problems. Proof-of-concept studies in mouse models of MPSI and MPSIIIA — which is caused by mutations in the gene encoding N-sulfoglucosamine sulfohydrolase gene — treated with lentiviral vector-modified HSPC gene therapy have shown increased efficiency of this approach over allogeneic HSCTPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXNpZ2FsbGk8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy
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ADDIN EN.CITE.DATA 170. Clinical trials aimed at correcting the neurological phenotype and systemic features of MPSI and MPSIIIA have recently started (Table 1). A preliminary communication on the MPSI gene therapy study shows supraphysiological blood IDUA activity, rapid reduction of GAG and early signs of clinical improvement ADDIN EN.CITE <EndNote><Cite><Author>Gentner</Author><Year>2019</Year><RecNum>808</RecNum><DisplayText><style face="superscript">171</style></DisplayText><record><rec-number>808</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1587046558">808</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gentner,B.</author></authors></contributors><titles><title>Extensive metabolic correction of Hurler Disease by hematopoietic stem cell-based gene therapy:preliminary results from a phase i/ii trial</title><secondary-title>Blood (supplement 1)</secondary-title></titles><pages>607
</pages><volume>134</volume><dates><year>2019</year></dates><urls></urls><electronic-resource-num>10.1182/blood-2019-128805</electronic-resource-num></record></Cite></EndNote>171.[H3] Other gene therapy strategiesClinical trials based on lentivirus-transduced HSPCs are ongoing for the lysosomal diseases cystinosis and Fabry disease (see Table 1) and are in the preclinical phase for MPS II, MPSIIIB, and Pompe disease. It should be noted that the benefits of ex vivo HSPC gene therapy might be limited in symptomatic patients and patients with rapidly progressive disease variants because of the inherent delay in the enzymatic reconstitution of CNS tissues by HSPC-derived myeloid cells. Approaches based on direct intra-brain delivery of adeno-associated virus (AAV) or lentiviral vectors encoding the gene encoding for the defective enzymePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZW5lZ2hpbmk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFy
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ADDIN EN.CITE.DATA 173 or the direct injection of gene modified haematopoietic progenitorsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXBvdG9uZG88L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy
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ADDIN EN.CITE.DATA 174 might provide more timely enzyme reconstitution. Universal newborn screening for early detection of these diseases is under development or already being implemented as part of established metabolic screening programmes and could allow for prompt treatment before onset of symptomsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZWFrZTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 175.[H2] Acquired diseases HSPCs could be exploited to deliver therapeutic molecules systemically or to affected tissues for the treatment of acquired diseases such as cancers, acquired immune disease, chronic infections or neurodegenerative disorders such as multiple sclerosis. HSPCs could be engineered to produce cytokines that induce resistance to specific microorganisms or express surface receptors that modulate the immune response; for example, when expressed on HSPCs, the immune checkpoint molecule PD-L1 was shown to inhibit autoimmune responses and reverted diabetes type 1 diabetes in an experimental modelPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW4gTmFzcjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+
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ADDIN EN.CITE.DATA 176. In addition, HSPC could produce molecules blocking tumor cell growth or facilitating immune recognition of cancer. Local release of therapeutic molecules delivered by HSPC could achieve sustained expression in target tissue while reducing systemic toxicity and the risk of adverse events. This was shown recently in preclinical models in which macrophage-infiltrating tumours derived from transduced HSPCs selectively expressing IFNα induced an immunostimulatory program in the tumour microenvironment, as shown by transcriptome analyses. This favored T cell priming and effector functions towards multiple tumor antigens, leading to inhibition of leukaemia growthPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fc2NvYmFyPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA 177.[H1] Conclusions and future perspectives HSPC gene therapy offers the prospect of major clinical improvement and even cure for a large number of inherited immunohaematological and metabolic diseases. As autologous HSPC gene therapy reaches the clinic, there are significant financial and logistical challenges that must be addressed before its use on a global scale. Current strategies are based on centralized manufacturing facilities and limited number of treatment centers expert in the disease and gene therapyGT, whereas fully automated transduction could modify this model by increasing local manufacturing and widespread diffusion. The development of stable producer cell lines and reagents capable of enhancing viral attachment (such as LentiBOOSTTM), and suppressing natural intracellular viral restriction pathways (such as Cyclosporin H), and promoting transduction while shortening ex vivo culture (such as PGE2), are under intense investigation, with some already in clinical use ADDIN EN.CITE <EndNote><Cite><Author>Gentner</Author><Year>2019</Year><RecNum>808</RecNum><DisplayText><style face="superscript">151,171</style></DisplayText><record><rec-number>808</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1587046558">808</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gentner,B.</author></authors></contributors><titles><title>Extensive metabolic correction of Hurler Disease by hematopoietic stem cell-based gene therapy:preliminary results from a phase i/ii trial</title><secondary-title>Blood (supplement 1)</secondary-title></titles><pages>607
</pages><volume>134</volume><dates><year>2019</year></dates><urls></urls><electronic-resource-num>10.1182/blood-2019-128805</electronic-resource-num></record></Cite><Cite><Author>Kanter J.</Author><Year>2019</Year><RecNum>757</RecNum><record><rec-number>757</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">757</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kanter J., Tisdale FJ., Mapara MY., Kwiatkowski JL., Krishnamurti L., Manfred Schmidt M., Miller AL., Pierciey FJ, Wenmei Huang W., Ribeil JA, Thompson AA, Walters MC.</author></authors></contributors><titles><title>Resolution of Sickle Cell Disease Manifestations in Patients Treated with Lentiglobin Gene Therapy: Updated Results from the Phase 1/2 Hgb-206 Group C Study</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>990</pages><volume>134 (Supplement_1)</volume><dates><year>2019</year></dates><urls></urls><electronic-resource-num> . Clonal tracking studies will be important to evaluate whether updated protocols preserve both primitive and committed progenitors in the drug product and favour rapid haematopoietic reconstitution, while simultaneously preventing rapid exhaustion of primitive HSCs and achieving long-term graft maintenance. Additionally, cryopreservation of the drug product or close automation of cell processing and transduction could allow greater standardization in terms of quality and dosing. For most HSCT applications, the reliance on alkylating agents for patient conditioning is associated with short-term and long-term toxicities. The development of antibody-based conditioning regimens targeting molecules expressed on host haematopoietic cells such as CD117 (c-Kit) or CD45 could replace alkylating agents or be used in conjunction with them to allow for a reduction in alkylating agent dose.Recent preclinical studies have shown a potential alternative to ex vivo gene transfer through transducing HSPCs after direct intravenous in vivo administration of viral vectors, albeit at low efficiency..178In some cases, the physiological regulation of transgene expression is desirable to achieve a clinical effect and to avoid unwanted, transgene-related toxicity. Although incorporation of sophisticated regulatory elements into gene-addition vectors may realize these criteria, locus-specific gene editing could harness natural gene regulatory mechanisms. However, the use of synthetic minigenes as ‘universal’ repair templates for homologous recombination will not necessarily recapitulate physiological gene expression and may require sophisticated design. Improvements in gene editing efficiency, particularly in repair accuracy, will likely translate into an increasing number of clinical applications using gene edited HSPCs. Although in principle gene editing should be safer than vector-based gene addition approaches as it should avoid issues with off-target DNA changes caused by semi-random vector integration, the clinical safety of gene editing in HSPC gene therapy has yet to be proven179PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Uc2FpPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 178. The development of high-fidelity Cas9 nucleases could overcome any residual off target changes, although DNA double-strand breaks can also cause genome rearrangements such as deletions, inversions and translocations ADDIN EN.CITE <EndNote><Cite><Author>Kosicki</Author><Year>2018</Year><RecNum>739</RecNum><DisplayText><style face="superscript">59</style></DisplayText><record><rec-number>739</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">739</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kosicki, M.</author><author>Tomberg, K.</author><author>Bradley, A.</author></authors></contributors><auth-address>Wellcome Sanger Institute, Hinxton, UK.</auth-address><titles><title>Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements</title><secondary-title>Nature biotechnology</secondary-title><alt-title>Nat Biotechnol</alt-title></titles><alt-periodical><full-title>Nat Biotechnol</full-title></alt-periodical><pages>765-771</pages><volume>36</volume><number>8</number><edition>2018/07/17</edition><keywords><keyword>Animals</keyword><keyword>*CRISPR-Cas Systems</keyword><keyword>*DNA Breaks, Double-Stranded</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mutagenesis</keyword><keyword>Polymerase Chain Reaction/methods</keyword><keyword>*Sequence Deletion</keyword></keywords><dates><year>2018</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1546-1696 (Electronic)
1087-0156 (Linking)</isbn><accession-num>30010673</accession-num><work-type>Letter
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ADDIN EN.CITE.DATA 62,63 hold promise for more safe and efficient genome engineering. Nevertheless, significant improvements in clinical-scale manufacturing and a better understanding of off-target and unexpected on-target effects are needed before implementation of gene editing in gene therapy. In the landscape of genome editing, preclinical studies and regulatory guidelines should be driven by previous experience from vector-based gene therapy, which has paved the way for the clinical translation of advanced cellular therapies. Assays and protocols must be adapted to better evaluate potential genotoxicity caused by gene editing.Most HSC gene therapies to date have targeted defined inherited diseases. As technology improves, and our understanding of the durability and safety of HSC gene therapy increases, opportunities may arise to target other disease settings. For example, acquired neurodegenerative conditions could benefit from sustained delivery of therapeutic molecules to the brain through HSPC-derived microglia. Chronic infectious diseases and cancer could also be ameliorated by systemic delivery of therapeutics, or through elimination of haematopoietic disease reservoirs as in the case of HIV180PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UZWJhczwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 179. The genetic modification of T lymphocytes with chimeric antigen receptor (CAR), for example, represents an innovative approach to treat various forms of haematological cancer181 ADDIN EN.CITE <EndNote><Cite><Author>June</Author><Year>2018</Year><RecNum>700</RecNum><DisplayText><style face="superscript">180</style></DisplayText><record><rec-number>700</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="0">700</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>June, C. H.</author><author>Sadelain, M.</author></authors></contributors><auth-address>From the Center for Cellular Immunotherapies, Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia (C.H.J.); and the Center for Cell Engineering, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York (M.S.).</auth-address><titles><title>Chimeric Antigen Receptor Therapy</title><secondary-title>The New England journal of medicine</secondary-title><alt-title>N Engl J Med</alt-title></titles><pages>64-73</pages><volume>379</volume><number>1</number><edition>2018/07/05</edition><keywords><keyword>*Adoptive Transfer/adverse effects</keyword><keyword>Antigens, CD19</keyword><keyword>Genetic Engineering</keyword><keyword>Humans</keyword><keyword>Neoplasms/*therapy</keyword><keyword>Receptors, Antigen, T-Cell/*therapeutic use</keyword><keyword>Recombinant Fusion Proteins/adverse effects/*therapeutic use</keyword><keyword>Remission Induction/methods</keyword><keyword>T-Lymphocytes/immunology/*transplantation</keyword></keywords><dates><year>2018</year><pub-dates><date>Jul 5</date></pub-dates></dates><isbn>1533-4406 (Electronic)
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GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat Biotechnol 33, 187-197, doi:10.1038/nbt.3117 (2015).179Tebas, P. et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected w182Schuessler-Lenz, M., Enzmann, H. & Vamvakas, S. Regulators' Advice Can Make a Difference: European Medicines Agency Approval of Zynteglo for Beta Thalassemia. Clin Pharmacol Ther 107, 492-494, doi:10.1002/cpt.1639 (2020).183Ledford, H. Quest to use CRISPR against disease gains ground. Nature 577, 156, doi:10.1038/d41586-019-03919-0 (2020).ith HIV. The New England journal of medicine 370, 901-910, doi:10.1056/NEJMoa1300662 (2014).180June, C. H. & Sadelain, M. Chimeric Antigen Receptor Therapy. The New England journal of medicine 379, 64-73, doi:10.1056/NEJMra1706169 (2018).181Schuessler-Lenz, M., Enzmann, H. & Vamvakas, S. Regulators' Advice Can Make a Difference: European Medicines Agency Approval of Zynteglo for Beta Thalassemia. Clin Pharmacol Ther 107, 492-494, doi:10.1002/cpt.1639 (2020).182Ledford, H. Quest to use CRISPR against disease gains ground. Nature 577, 156, doi:10.1038/d41586-019-03919-0 (2020).AcknowledgementsThe authors thank Fondazione Telethon, European Community (SCIDNET, E-rare EUROCID) for support. AA is the recipient of the Else Kr?ner Fresenius Prize for Medical Research 2020. A.J.T. is supported by the Wellcome Trust and the National Institute for Health Research Biomedical Research Centres at the Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. A.A. and A.T. are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (Project ID No 739543) and Inborn Error Working Party of EBMT. The authors thank Dr. F. Tucci for her help with the preparation of Table 1 and Dr. M.E. Bernardo, Dr. F. Fumagalli, Dr. A. Gritti, and Dr. S. Scala, for their critical review of the figures and manuscript.Author contributionsAll authors researched the literature, provided substantial contributions to discussions of the content, and reviewed and/or edited the manuscript before submissionCompeting interestsThe San Raffaele Telethon Institute for Gene Therapy (SR-TIGET) is a joint venture between Fondazione Telethon and Ospedale San Raffaele (OSR). Gene therapies for ADA-SCID, Wiskott-Aldrich syndrome (WAS), metachromatic leukodystrophy (MLD), β-thalassemia (BTHAL) and Mucopolysaccharidosis I (MPSI) developed at SR-TIGET were licensed to Orchard Therapeutics (OTL) in 2018 and 2019. A. A. is the PI of the above clinical trials. A.J.T has equity in and is in the scientific advisory board for OTL and receives consultancy payments from Rocket pharmaceuticals.Peer review informationNature Reviews Genetics thanks James Davies, Jose Carlos Segovia and Troy C. Lund for their contribution to the peer review of this work.Table 1. Ongoing clinical trials for monogenic disorders using ex vivo HSPC gene therapy. Clinical trial registry numbers (trial phase)Disease (defective gene)Conditioning intensity and chemotherapyCorrective strategy NCT03311503 (I/II), NCT03601286 (I/II)SCID-X1 (IL2RG)Low-dose busulfanAutologous CD34+ cells transduced with the G2SCID lentiviral vectorNCT03217617 (I/II)SCID-X1 (IL2RG)Not knownAutologous CD34+ cells transduced with the self-inactivating lentiviral vector TYF-IL-2RgNCT01306019 (I/II)SCID-X1 (IL2RG)Low-dose busulfanAutologous CD34+ cells transduced with the VSV-G pseudotyped lentiviral CL20- 4i-EF1a-hyc-OPT vectorNCT02999984 (I/II), NCT03765632 (I/II), NCT04140539 (II/III)ADA-SCID (ADA)Low-dose busulfanCryopreserved autologous CD34+ cells treated with an EFS-ADA lentiviral vector (OTL-101)NCT03645460 (N/a)ADA-SCID (ADA)Not knownAutologous CD34+ cells transduced with the improved self-inactivating lentiviral vector TYF-ADANCT01515462 (I/II)NCT03837483 (II)WAS (WAS)Reduced-intensity (busulfan and fludarabine)Autologous CD34+ hematopoietic stem cells transduced ex vivo with a lentiviral vector carrying WAS (OTL-103)NCT01410825 (I/II), NCT02333760 (I/II) WAS (WAS)Myeloablative (busulfan and fludarabine)Autologous CD34+ hematopoietic stem cells transduced with the lentiviral vector w1.6W NCT01347346 (I/II), NCT01347242 (I/II) WAS (WAS)Myeloablative (busulfan and fludarabine)Autologous CD34+ cells transduced with a lentiviral vector carrying WASNCT01855685 (I/II), NCT02234934 (I/II)X-CGD (CYBB)Myeloablative (busulfan)Autologous CD34+ cells transduced with a lentiviral vector carrying human gp91phox (OTL-102)NCT02757911 (I/II)X-CGD (CYBB)Myeloablative (busulfan)Autologous CD34+ cells transduced with the G1XCGD lentiviral vectorNCT03812263 (I/II), NCT03825783 (I)LAD (CD18)Myeloablative (busulfan)Autologous CD34+ cells transduced with the lentiviral vector Chim-CD18-WPRE, which carries the ITGB2 gene NCT03538899 (I/II)ART-SCID (DCLRE1C)Sub-myeloablative (busulfan)Autologous CD34+ cells transduced with the self-inactivating lentiviral vector AProArt, carrying the corrected DCLRE1C gene NCT02906202 (III), NCT03207009 (III)TBT (HBB)Myeloablative (busulfan)Autologous CD34+ cells transduced with a lentiviral βA-T87Q-globin vectorNCT02453477 (I/II)TBT (HBB)Myeloablative (treosulfan and thiotepa)Autologous CD34+ cells transduced with the GLOBE lentiviral vector (OTL-300)NCT03655678 (I/II)TBT (HBB)Myeloablative (busulfan)Gene editing of the erythroid enhancer of BCL11A using CRISPR-Cas9 to increase HbF expression NCT03432364 (I/II)TBT (HBB)Myeloablative (busulfan)Gene editing of the erythroid enhancer of BCL11A using zinc finger nucleasesNCT02151526 (I/II), NCT02140554 (I/II)SCD (HBB)Myeloablative (busulfan)Autologous CD34+ cells transduced with a lentiviral βA-T87Q globin vector (LentiGlobin BB305 Drug Product)NCT02186418 (I/II)SCD (HBB)Reduced intensity (melphalan)Autologous CD34+ cells transduced with a γ-globin lentiviral vector (ARU-1801)NCT03964792 (I/II)SCD (HBB)Not knownAutologous CD34+ cell transduced with the GLOBE1 lentiviral vector, which carries the βAS3 globin gene (DREPAGLOBE)NCT02247843 (I/II)SCD (HBB)Myeloablative (busulfan)Autologous CD34+ cells transduced with the Lenti/G-βAS3-FB lentiviral vectorNCT03282656 (I)SCD (HBB)Myeloablative (busulfan)CD34+ cells transduced with a lentiviral vector containing a short-hairpin RNA targeting BCL11A to increase HbF expressionNCT04091737 (I)SCD (HBB)Reduced intensity (melphalan)Autologous CD34+ cells transduced with a lentiviral vector encoding human γ-globin G16D and a short-hairpin RNA (RNA734) targeting the hypoxanthine guanine phosphoribosyltransferase gene HPRT (CSL200)NCT03745287 (I/II)SCD (HBB)Myeloablative (busulfan)Gene editing of the erythroid enhancer of BCL11A using CRISPR-Cas9 to increase HbF expression NCT03157804 (I/II), NCT04069533 (II), NCT01331018 (I), NCT03814408 (I)Fanconi anaemia type A (FANCA)No conditioningAutologous CD34+ cells transduced with a lentiviral vector carrying FANCA NCT03351868 (N/a)Fanconi anaemia type A (FANCA)Not knownAutologous hematopoietic stem cells and mesenchymal stem cells transduced with a lentiviral vector carrying FANCANCT04105166 (I)PKD (PKLR)Not knownAutologous CD34+ cells transduced with a lentiviral vector containing PKLR (RP-L301)NCT01560182 (I/II), NCT03392987 (II)MLD (ARSA)Myeloablative (busulfan)Autologous CD34+ cells transduced with a lentiviral vector encoding human ARSA cDNA (OTL-200, Libmeldy)NCT01896102 (II/III)X-ALD (ABCD1)Myeloablative (busulfan and cyclophosphamide)Autologous CD34+ cells transduced with the self-inactivating lentiviral vector MNDprom-ABCD1 Lenti-D NCT03852498 (III)X-ALD (ABCD1)Myeloablative (busulfan and fludarabine)Autologous CD34+ cells transduced with the self-inactivating lentiviral vector MNDprom-ABCD1 Lenti-D NCT03488394 (I/II)MPSI (IDUA)Myeloablative (busulfan and fludarabine)Autologous CD34+ cells transduced with a lentiviral vector carrying human IDUA (OTL-203)NCT04201405 (I/II)MPSIIIA (SGSH)Myeloablative (busulfan)Autologous CD34+ cells transduced with a lentiviral vector carrying human SGSHNCT03897361 (I/II)Cystinosis (CTNS)Myeloablative (busulfan)Autologous CD34+ cells transduced with a pCCL-CTNS lentiviral vector carrying the human CTNS cDNA sequenceNCT02800070 (I), NCT03454893 (I/II)Fabry disease (GLA)MyeloablativeAutologous CD34+ cells transduced with the lentivirus vector AVR-RD-01 carrying GLAData taken from a search performed on April 2020 for studies based on “hematopoietic stem cell” and “gene therapy” or “gene editing”, and “genetic diseases” on that are currently active (recruiting or not). Studies for which information has not been updated in the past 2 years have not been considered. SCID-X1, X-linked severe combined immunodeficiency; ADA-SCID, adenosine deaminase deficient severe combined immunodeficiency; N/a, trials without FDA-defined phases; WAS, Wiskott-Aldrich syndrome; X-CGD, X-linked chronic granulomatous disease; LAD, leukocyte adhesion deficiency; ART-SCID, ARTEMIS-deficiency severe combined immunodeficiency; TBT, transfusion-dependent β-thalassaemia; HbF, foetal haemoglobin; SCD, sickle cell disease; PKD, pyruvate kinase deficiency; MLD, metachromatic leukodystrophy; X-ALD, X-linked adrenoleukodystrophy; MPSI, mucopolysaccharidosis type I; MPSIIIA, mucopolysaccharidosis type IIIA.Figure 1. The haematopoietic hierarchy and genetic disorders. Bone marrow resident hematopoietic stem cells (HSCs) and progenitor cells replenish blood and tissues with new mature cells. Both HSCs and haematopoeitic progenitor cells express the cell surface marker CD34, which is used to enrich for a mixture of hematopoietic stem and progenitor cells (HSPCs) for transplantation and gene therapy. HSCs can be classed as long-term hematopoietic stem cells (LT-HSC) or short term hematopoietic stem cells (ST-HSC). ST-HSCs progressively acquire lineage specifications in order to differentiate into lineage committed progenitors and eventually terminally differentiated cells, which are released into the peripheral blood. A simplified scheme of human haematopoiesis is presented here. Alternative models have been postulated based on cell surface marker analyses, in vitro and in vivo functional assays, clonal tracking by insertion analyses in HSPC gene therapy studies and single cell RNA analyses (reviewed in ref.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZXJydWE8L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 22). Mendelian genetic disorders can affect self-renewal, differentiation and/or the function of different blood and immune cells. Examples of genetic diseases for which gene therapy is under investigation or are approved are represented in white boxes. MPP, multipotent progenitor; MEP, megakaryocytic-erythroid progenitor; CMP, common myeloid progenitor; GMP, granulomonocytic progenitor; LMMP, lymphoid-myeloid primed progenitor; CDP, common dendritic progenitor; CLP, common lymphoid progenitor; preB, pre-B cell; PreT, pre-T cell; NK, natural killer; SCID; severe combined immunodeficiency; CID, combined immunodeficiency. *Wiskott-Aldrich syndrome affects platelets and other lineages.Figure 2. Timeline of progress of HSPC gene therapy Progress of HSPC gene therapy for monogenic disorders and enabling development in technology. Data for figure:YearTextReferences1980Development of recombinant viral vectors 30,311990First gene therapy approved in humans, for the treatment of ADA-SCID using engineered peripheral blood lymphocytes9, 10, 121992-1995First gene therapy attempt using hematopoietic progenitors, employing bone marrow/cord blood progenitors for ADA-SCID9, 111996A self-inactivating lentiviral vector proves highly effective in transferring genes to HSPCs in preclinical studies322000-2004First demonstration of clinical benefit using HSPC gene therapy for SCID-X113, 892002First use of patient conditioning in HSPC gene therapy, using low-intensity conditioning in patients with ADA-SCID142003-2006Insertional mutagenesis observed in clinical trials for SCID-X1 linked to leukaemia cases 16, 152006-2014Insertional mutagenesis after HSPC gene therapy in X-linked chronic granulomatous disease and Wiskott-Aldrich syndrome using gammaretroviral vectors limiting its clinical benefit 110, 1112009First clinical use of lentiviral vectors, for treatment of X-linked adrenoleukodystrophy332014First trials of gene editing in human T cells for the treatment of HIV-1 infection1792013Demonstration of efficacy in HSPC gene therapy using lentiviral vectors for metachromatic leukodystrophy 702013-2015Demonstration of efficacy in HSPC gene therapy using lentiviral vectors for Wiskott-Aldrich syndrome 116, 912016HSPC gene therapy for ADA-SCID approved in the EU1352018-2019Efficacy of HSPC gene therapy shown for β-thalassemia24, 252019HSPC gene therapy for β-thalassemia is approved in the EU ADDIN EN.CITE <EndNote><Cite><Author>Schuessler-Lenz</Author><Year>2020</Year><RecNum>848</RecNum><DisplayText><style face="superscript">181</style></DisplayText><record><rec-number>848</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1600206415">848</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schuessler-Lenz, M.</author><author>Enzmann, H.</author><author>Vamvakas, S.</author></authors></contributors><auth-address>European Medicines Agency (EMA) Committee for Advanced Therapies, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany.
European Medicines Agency (EMA) Committee for Human Medicinal Products, Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM), Bonn, Germany.
Product Development Scientific Support Department, European Medicines Agency (EMA), Amsterdam, The Netherlands.</auth-address><titles><title>Regulators' Advice Can Make a Difference: European Medicines Agency Approval of Zynteglo for Beta Thalassemia</title><secondary-title>Clin Pharmacol Ther</secondary-title></titles><periodical><full-title>Clin Pharmacol Ther</full-title></periodical><pages>492-494</pages><volume>107</volume><number>3</number><edition>2019/11/11</edition><dates><year>2020</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1532-6535 (Electronic)
0009-9236 (Linking)</isbn><accession-num>31705534</accession-num><urls><related-urls><url> proof of principle study for the use of HSPC gene therapy in treating Fanconi Anemia272019First gene editing clinical trials start in human HSPCs ADDIN EN.CITE <EndNote><Cite><Author>Ledford</Author><Year>2020</Year><RecNum>849</RecNum><DisplayText><style face="superscript">182</style></DisplayText><record><rec-number>849</rec-number><foreign-keys><key app="EN" db-id="rptaptfsqaxx95et5pxxxtxuvt0azxer2paa" timestamp="1600206816">849</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ledford, H.</author></authors></contributors><titles><title>Quest to use CRISPR against disease gains ground</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>156</pages><volume>577</volume><number>7789</number><edition>2020/01/09</edition><keywords><keyword>CRISPR-Cas Systems</keyword><keyword>Clustered Regularly Interspaced Short Palindromic Repeats</keyword><keyword>*HIV Infections</keyword><keyword>Humans</keyword><keyword>*Precursor Cell Lymphoblastic Leukemia-Lymphoma</keyword><keyword>Stem Cells</keyword><keyword>*Biological techniques</keyword><keyword>*CRISPR-Cas9 genome editing</keyword><keyword>*Medical research</keyword></keywords><dates><year>2020</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1476-4687 (Electronic)
0028-0836 (Linking)</isbn><accession-num>31911695</accession-num><urls><related-urls><url> 3. Manufacturing of engineered HSPC by gene addition and gene editing. Autologous HSPCs are collected from the patient through multiple aspirations from the iliac crests or by leukapheresis following the administration of growth factor and chemokine antagonist. The collected material is enriched for CD34+ cells cultured in the presence of cytokines and genetically modified either by gene addition using gammaretroviral or lentiviral vectors or gene editing using zinc finger, CRISPR/Cas9 or transcription activator-like effector nuclease (TALEN) programmable endonucleases. Before gene therapy, patients are usually administered a conditioning preparatory regimen to deplete endogenous HSPCs. The intensity of conditioning ranges from reduced intensity to myeloablative, depending on the disease and the engraftment level required to reach the therapeutic threshold. The medicinal product is represented by the gene-corrected cells, ready for infusion at the end of the manipulation or after a cryopreservation and thawing step. Quality control tests performed on the drug product may include those on viability, sterility, endotoxin level, mycoplasma, immune phenotype, number of vector copies per genome, transduction efficiency, transgene expression vector, production contaminants and replication competent vector. In the case of fresh product or rapidly progressive diseases, a two-step strategy is employed to allow urgent treatment without completing all tests. Adapted from ref. X, Springer Nature Limited.Figure 4. HSPC gene therapy vector design and integration preferences A) Structure of the murine leukaemiavirus (MLV) gammaretrovirus and human immunodeficiency virus (HIV) lentivirus genomes and derived vectors. Gammaretroviral vectors (gRV) harbour a viral promoter in the U3 region of the 5’ long terminal repeat (LTR). In self-inactiving gammaretroviral (SIN-RV) and self-inactivating lentiviral (SIN-LV) vectors, deletions in the U3 region abolish the viral promoter and the expression of the therapeutic transgene is instead driven by a promoter — generally of cellular origin — placed between the two LTRs. Diseases for which each vector is being investigated and the corresponding therapeutic genes are shown. RRE; Rev responsive element. B) Differential distribution of MLV and HIV integration sites in the human genome is dictated by factors assembled in the pre-integration complex tethering the vector DNA to specific chromatin regions. MLV-derived vectors preferentially integrate into promoters and enhancers, whereas lentiviral vectors integrate into active gene bodies. Key proteins interacting with the MLV pre-integration complex (PIC) and influencing integration pattern of gRV and SIN-RV are the bromodomain/extraterminal domain proteins (BETs). The lens epithelium-derived growth factor (LEDGF/p75) mediates tethering of the lentiviral PIC to transcribed gene regions. Arrows indicate vector integration sites. Part B adapted with permission from ref. X, Elsevier.Figure 5. Gene editing techniques for HSPC gene therapyMolecular tools for gene editing include zinc finger nucleases, transcription activator-like effector nucleases (TALENs) and CRISPR-Cas9, which introduce targeted double-stranded DNA breaks (DSBs) into the genome. The cell repairs the DNA breaks by non-homologous end joining (NHEJ), potentially introducing small insertions and deletions (INDELs), or by homology-directed repair (HDR) if a suitable donor template is provided. Examples of gene editing approaches for the treatment of haemoglobinopathies are shown. HDR-driven strategies include correction of SNPs in the HBB gene locus to reverse red blood cell (RBC) sickling in sickle cell disease (SCD) or the targeted addition of HBB to treat either SCD or β-thalassaemia. NHEJ-driving strategies include the generation of mutations in the β-globin locus that mimic hereditary persistence of foetal haemoglobin (HPFH) and the inhibition of the expression of BCL11A, the main repressor of foetal HBG1/HBG2 genes, both resulting in the expression of foetal haemoglobin and amelioration of the disease phenotype. Elements of this figure are adapted with permission from ref X, Cell Press.Figure 6. HSPC‐driven localized delivery of therapeutics in lysosomal storage diseases. Gene-corrected hematopoietic cells can release functional enzyme into the circulation and at a local level following migration into the tissue, such as the liver, spleen, bone, heart, kidney and peripheral nervous system (REF. 77, 164, 169, 170). In lysosomal storage enzyme diseases, substrate accumulation in cells of the central and peripheral nervous system leads to demyelination and cognitive and motor degeneration. In order to reach the CNS, cells need to cross the blood–brain barrier, which can be facilitated by chemotherapy (lightning bolt) and in some cases the underlying disorder. HSPCs may directly engraft in the CNS, expand locally and differentiate into corrected myeloid and microglia-like cells, which then release the therapeutic enzyme (REF. 78). In addition, corrected monocytes released from the bone marrow may migrate into the CNS, differentiate into macrophages and produce enzymes locally. The relative contribution of HSPC and mature cells to correction is still unclear (ref. 164). Therapeutic enzymes can be taken up by non-corrected cells expressing the mannose–phosphate receptor, including resident cells of the CNS, and break down accumulated substrates. Gene therapy may allow superior clearance of the accumulated substrates in the target organ compared with allogeneic HSPC transplantation, and replacement therapies that use enzymes that do not cross the blood–brain barrier.GLOSSARY AllogeneicRelating to or denoting that the source of cells, tissues or organs for transplant is from a genetically different individual than the recipient.Primary immunodeficienciesMendelian genetic disorders caused by defects in the development and/or function of immune cells. Currently, more than 300 genes have been identified that cause adaptive and/or innate immune cell defects.Chronic granulomatous disease Or CGD. A disease caused by dysfunction of the phagocyte NADPH-oxidase, a membrane-bound enzyme complex required for effective killing of bacteria and fungi.LeukapheresisA procedure that separates white blood cells including haemotopoeitic stem cells from the blood. White cells are collected from the donor and other blood fractions are returned to the circulation.Mobilizing agentsDrugs that induce transient mobilization of haematopoeitic stem cells from the bone marrow to the circulation so that they can be collected by leukapheresis.Myeloablative conditioningHigh-dose chemotherapy that destroys hematopoietic cells in the bone marrow and severely reduces the number of blood cells. Usually followed by HSPC transplantation or gene therapy to rebuild the bone marrow.OligoclonalityA quality associated with clones derived from one or a few cells or molecules. Iron chelation therapyPharmacological depletion of toxic iron accumulation in organsStress erythropoiesisThe rapid development of new red blood cells stimulated in response to acute anaemia ................
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