Delayed Degeneration of Synaptic Terminals in the Striatum ...



Counting the cost of spinal muscular atrophy Thomas H. Gillingwater1,2*1Euan MacDonald Centre for Motor Neurone Disease Research & 2Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK* Corresponding Author:Professor Thomas H. GillingwaterEdinburgh Medical School: Biomedical SciencesUniversity of Edinburgh EdinburghEH8 9AGUKEmail: T.Gillingwater@ed.ac.ukTel: +44 (0)131 6503724Fax?: +44 (0)131 6504193COMMENTARY/EDITORIALSpinal muscular atrophy (SMA) is a predominantly childhood neuromuscular disease, representing one of the most common genetic causes of infant mortality. The degeneration of lower motor neurons that occurs in SMA leads to a progressive decline in muscle strength [1-3]. However, the profile of disease progression varies substantially between patients, resulting in the identification of as many as 5 distinct clinical subgroups (referred to as Type 0 through to Type IV) [4]. Type 1 SMA, otherwise known as Werdnig-Hoffman disease, is the most common form of the disease, with onset occurring by 6 months of age. Difficulties with feeding and breathing contribute to premature death, normally occurring within the first two years of life in the absence of palliative care [5].Exciting developments in the field of molecular genetic research over the last couple of decades have firmly established the cause of SMA for the vast majority of patients: low expression levels of survival motor neuron (SMN) protein resulting from mutations in the survival motor neuron (SMN1) gene [1,2]. The subsequent generation of genetically-accurate animal models of SMA has led to the identification of key events occurring during disease pathogenesis [2,3,6,7]. In turn, this has resulted in the development of potential disease-modifying therapies for SMA. Several different strategies have successfully demonstrated that restoring levels of SMN protein during critical developmental time-windows (through the use of gene therapy, antisense oligonucleotide treatment or small molecule approaches) leads to a robust amelioration of disease symptoms and significant extension of life span in animal models [for reviews see 5,8,9]. A second generation of SMN-independent therapies are also currently progressing through pre-clinical development, targeting a range of other molecular pathways with the potential to further modify disease. These include therapies targeting muscle strength [10], Rho-kinase (ROCK) pathways [11], and ubiquitination pathways [12-13]. Taken together, these developments have raised considerable excitement amongst the SMA patient and research communities, encouraging the belief that disease-modifying therapies are near.The strong pre-clinical data from animal models has resulted in several human patient clinical trials for SMA being established over the last few years. Although none have yet proceeded through all stages of the full clinical trial process required in order to receive full regulatory approval, initial signs have been encouraging, especially for trials using gene therapy or antisense oligonucleotide treatment to increase SMN levels [14]. Although full clinical data are not yet available, it appears likely that at least one of these approaches will result in the first disease-modifying therapy for SMA. The extent to which these treatment strategies modulate a patient’s disease phenotype remains to be clarified, although they are unlikely to represent a full ‘cure’ [8]. Nevertheless, the encouraging findings from ongoing clinical trials raise the likelihood that a disease-modifying therapy will be made available to clinicians caring for SMA patients in the medium- to long-term. This raises a large number of potential financial, logistical and ethical issues that have not previously been considered relevant to SMA.Previous, largely qualitative studies have highlighted the high levels of burden that are experienced by individuals with SMA and their families, impacting across all aspects of daily life [15]. The emotional and social costs of SMA are therefore relatively well documented and not to be underestimated. However, until recently, very few studies have attempted to establish the economic/financial costs of SMA. One area where the economic/financial costs of SMA have previously been studied is with regards to the cost effectiveness of universal prenatal screening for SMA (one suggested intervention to reduce disease incidence). For example, a recent study by Little and colleagues suggested a cost of $5.0 million per case averted [16]. However, more broad-reaching studies examining the total costs of care for SMA patients are likely to be more relevant to the pharmaceutical industry and for future policy and funding decisions made by healthcare regulators that will determine access to, and provision of, new disease-modifying therapies for SMA.In the current issue of Journal of Medical Economics, Armstrong and colleagues report on an important study of the economic/financial costs of SMA, based on Department of Defense Military Healthcare System (MHS) data spanning from 2003-2012 [17]. By comparing healthcare costs of more than 200 SMA patients with those of more than 700 individuals belonging to a comparator cohort (selected using a 3:1 match based on age and gender), they revealed a significant increase in total expenditure for SMA patients. For example, the median total expenditure for SMA patients over an average of ~7 years was $83,652, almost $80,000 higher than the total expenditure recorded for the comparator group. As expected, further stratification of these data to examine costs specifically in SMA patients with more severe forms of the disease (likely to represent Type I SMA patients, although information on the precise clinical diagnosis wasn’t available to the researchers) identified even higher costs (median cost of $167,921). Although this study has several limitations (acknowledged by the authors), including a lack of detailed patient information to facilitate accurate grouping of patients by disease sub-type and absence of information concerning additional financial costs beyond those recorded in the MHS records resulting in a likely underestimate of the full economic/financial costs encountered, the authors have provided invaluable insights into the real-world costs of healthcare for SMA. The costs identified in the Armstrong et al study [17] are specifically related to those incurred by accessing healthcare provision available in the United States of America. It is therefore of interest to make comparisons with a near-contemporaneous study from Klug and colleagues reporting on the economic burden of SMA in Germany [18]. This study examined a similar number of SMA patients (just under 200 in total), covering SMA Types I to III in patients from birth through to 73 years of age. They estimated that the average annual ‘cost of illness’ (COI) for each patient in 2013 was €70,566. As in the Armstrong et al study, the highest costs were incurred in patients with SMA Type I (increasing to €107,807 per year). Interestingly, informal care costs and indirect costs incurred by patients and their caregivers (factors that were likely to be underestimated in the Armstrong et al study) contributed significantly to the overall COI in Germany. Taken together, these two recent studies reveal that the high economic/financial costs of SMA are not associated with just one specific healthcare system, being replicated across multiple countries. It is of note, therefore, that the estimated total economic burden of SMA in Germany is ~€106.5 million per year [18]. The total economic burden in larger countries, such as the United States of America, is therefore likely to be proportionately higher.Although the burden of SMA cannot, and should never be, reduced to an analysis of economic/financial cost, the insights provided by studies such as those from Armstrong and colleagues will contribute significantly to our understanding of the full societal impact of diseases such as SMA, helping to inform and guide therapy development and provision over the coming years.CONFLICT OF INTEREST STATEMENTThe author is Chair of the Scientific Advisory Board of the SMA Trust and is named on a patent application submitted by the University of Edinburgh for the use of beta-catenin inhibitors for the treatment of SMA. REFERENCES1. Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, et al. (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell, 80, 155-165.2. Burghes AH, Beattie CE (2009) Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat. Rev. Neurosci., 10, 597-609.3. Hamilton G, Gillingwater, TH (2013) Spinal muscular atrophy: going beyond the motor neuron. Trends Mol. Med., 19, 40-50.4. Mercuri E, Bertini E, Iannaccone ST. (2012) Childhood spinal muscular atrophy: controversies and challenges. Lancet Neurol., 11, 443-452.5. Faravelli I, Nizzardo M, Comi GP, Corti S. (2015) Spinal muscular atrophy--recent therapeutic advances for an old challenge. Nat. Rev. Neurol., 11, 351-359.6. Tisdale S, Pellizzoni L. (2015) Disease mechanisms and therapeutic approaches in spinal muscular atrophy. J. Neurosci., 35, 8691-8700.7. Shababi M, Lorson CL, Rudnik-Sch?neborn SS. (2014) Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J. Anat., 224, 15-28.8. Wirth B, Barkats M, Martinat C, Sendtner M, Gillingwater TH. (2015) Moving towards treatments for spinal muscular atrophy: hopes and limits. Expert Opin. Emerg. Drugs, 20, 353-356.9. Beaudet AL, Meng L. (2016) Gene-targeting pharmaceuticals for single-gene disorders. Hum. Mol. Genet., 25, R18-26.10. Ripolone M, Ronchi D, Violano R, Vallejo D, Fagiolari G, Barca E, Lucchini V, Colombo I, Villa L, Berardinelli A, Balottin U, Morandi L, Mora M, Bordoni A, Fortunato F, Corti S, Parisi D, Toscano A, Sciacco M, DiMauro S, Comi GP, Moggio M. (2015) Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy. JAMA Neurol., 72, 666-675.11. Bowerman M, Beauvais A, Anderson CL, Kothary R. (2010) Rho-kinase inactivation prolongs survival of an intermediate SMA mouse model. Hum. Mol. Genet., 19, 1468-1478.12. Wishart TM, Mutsaers CA, Riessland M, Reimer MM, Hunter G, Hannam ML, Eaton SL, Fuller HR, Roche SL, Somers E, Morse R, Young PJ, Lamont DJ, Hammerschmidt M, Joshi A, Hohenstein P, Morris GE, Parson SH, Skehel PA, Becker T, Robinson IM, Becker CG, Wirth B, Gillingwater TH. (2014) Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy. J. Clin. Invest., 124, 1821-1834.13. Groen EJ, Gillingwater TH. (2015) UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration. Trends Mol. Med., 21, 622-632.14. Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC, Norris DA, Bennett CF, Bishop KM. (2016) Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy. Neurology., 86, 890-897.15. Qian Y, McGraw S, Henne J, Jarecki J, Hobby K, Yeh WS. (2015) Understanding the experiences and needs of individuals with Spinal Muscular Atrophy and their parents: a qualitative study. BMC Neurol., 15, 217.16. Little SE, Janakiraman V, Kaimal A, Musci T, Ecker J, Caughey AB. (2010) The cost-effectiveness of prenatal screening for spinal muscular atrophy. Am. J. Obstet. Gynecol., 202, 253 e1-7.17. Armstrong EP, Malone DC, Yeh WS, Dahl GJ, Lee RL, Sicignano N. (2016) The Economic Burden of Spinal Muscular Atrophy. J. Med. Econ., [Epub ahead of print]18. Klug C, Schreiber-Katz O, Thiele S, Schorling E, Zowe J, Reilich P, Walter MC, Nagels KH. (2016) Disease burden of spinal muscular atrophy in Germany. Orphanet J. Rare Dis., 11, 58. ................
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