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function of motor neurons and other cell types throughout their lives. Presymptomatically, nusinersen-treated newborns with three SMN2 copies show motor development similar to that of healthy children, in contrast to newborns with only two SMN2 copies. The latter underperformed in comparison with the natural development of healthy controls, clearly demonstrating that intrathecal injection of nusinersen is not sufficient to fully counteract SMA (38). Moreover, there is still little knowledge of the long-term effects of nusinersen or onasemnogene abeparvovec therapy. Therefore, patients need to be clinically followed over a reasonable period (6–10 years), with special emphasis on cognitive abilities, social integration, and heart development. Doing so would allow the identification of potential problems and the adoption of precautionary measures if needed. Approximately 10,000 SMA patients are currently being treated with nusinersen, and several hundred have been treated with onasemnogene abeparvovec. All patients appear to have benefited from the therapy, by either stabilizing or improving the phenotype. However, patients with only two SMN2 copies in particular might develop new phenotypes not previously seen due to the early lethality of SMA type I and may need additional SMN-independent therapy. Combinatorial Therapies SMN protein is essential for every cell. Therefore, it is likely that in individuals with only two SMN2 copies, even if they are treated presymptomatically with nusinersen or systemically with onasemnogene abeparvovec (which is diluted with every cell division), the SMN may be insufficient for dividing cells. Risdiplam may be an option to support all other cell types systemically. However, clinical trials are not yet complete, and therefore it is premature to conclude that a combination of nusinersen, onasemnogene abeparvovec, and/or risdiplam is the ultimate solution. It still might be that SMN-independent therapies are necessary, such as a decrease of the protective www.annualreviews.org • 25 Years of Spinal Muscular Atrophy Research 251 Annu. Rev. Genom. Hum. Genet. 2020.21:231-261. Downloaded from www.annualreviews.org Access provided by 2600:1700:3c30:a3d0:89dc:b3d1:ac73:5085 on 01/23/22. For personal use only. SMA modifiers NCALD or CHP1 or an increase of PLS3 (71, 84, 87, 142, 169) or the restoration of the calcium level by the troponin activator reldesemtiv (7). Carrier Screening More and more carriers will be identified, either by screening programs such as those in Israel and Taiwan or in diagnostic settings based on exome and genome screens in the future. How a couple with a 25% a priori risk of having a baby with SMA will make a decision in the future is difficult to predict. However, the decision might strongly depend on whether SMA becomes curable (as opposed to treatable) along with, most likely, the future costs of therapy. Ethical and Financial Issues Currently, the cost of Spinraza is approximately $400,000–500,000 (or €400,000–500,000) in the first year and $250,000–300,000 (or €250,000–300,000) per year for the duration of the patient’s lifetime. The cost of Zolgensma is $2 million for a single injection. These prices are not affordable for any health-care providers in the long run. With the increasing number of therapies for rare diseases, in the near future, an ethical and thoughtful consideration of all players (industry, the health-care system, patients, and caregivers) will be crucial. DISCLOSURE STATEMENT B.W. and N.M.-F. are inventors on patent applications related to SMA gene modifiers, NCALD, and/or CHP1. ACKNOWLEDGMENTS This work was supported by an NRW Innovation Award (B.W.), the Deutsche Forschungsgemeinschaft (Wi945/17-1, Wi945/18-1, Wi945/19-1, and RTG1960 to B.W. and KY96/1-2 to M.J.K.), SMA Europe (M.J.K.), Cure SMA (B.W.), and the Center for Molecular Medicine Cologne [C16 (2017–2019) to B.W. and M.K. and C18 (2020–2023) to B.W.]. LITERATURE CITED 1. Ackermann B, Krober S, Torres-Benito L, Borgmann A, Peters M, et al. 2013. Plastin 3 ameliorates spinal muscular atrophy via delayed axon pruning and improves neuromuscular junction functionality. Hum. Mol. Genet.
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