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22nd International SMA Researcher Meeting, Dallas, Texas, USA, June 14–16, 2018). SRK-015 (Scholar Rock) is a highly selective monoclonal antibody that acts as an inhibitor of latent myostatin (136). Preclinical studies demonstrated that it efficiently promotes muscle cell growth and differentiation, increases muscle function, and improves the bone phenotype of SMA mouse models (49, 105). The safety, pharmacokinetics, and pharmacodynamics of increasing SRK015 doses are being assessed in a phase 1, randomized, placebo-controlled trial. Recent interim results validate its safety and efficacy in a once-every-four-weeks dosing regimen. Specifically, after a single dose of SRK-015 (10, 20, or 30 mg/kg), serum levels of latent myostatin were significantly increased and sustained over almost three months (Y. Chyung, unpublished results reported at the 23rd International SMA Researcher Meeting, Anaheim, California, USA, June 27–30, 2019). THE FUTURE OF SPINAL MUSCULAR ATROPHY SCREENING AND TREATMENT Newborn Screening All preclinical and clinical studies have shown that early therapeutic intervention, preferably presymptomatically, achieves the best results. The most recent studies on autopsy material from SMA and control individuals have shown that SMN levels are highest prenatally, drastically decline postnatally, and further drop after three months of age. These findings emphasize the need for SMN immediately after birth, or even prenatally (139). Strikingly, neurofilament levels at birth are already greatly increased in SMA patients with two SMN2 copies, strongly hinting at increased axonal degradation (36). Therefore, newborn screening is essential to identify individuals carrying homozygous SMN1 deletions and to start treatment in the presymptomatic phase. Based on the neurofilament data, for individuals with two SMN2 copies, the notion of “presymptomatic” is already questionable. In the United States, Belgium, Australia, and Germany, newborn screening either has been introduced nationwide or will be introduced soon. In the United States, newborns with four SMN2 250 Wirth et al. 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. copies are not directly included in therapy but are followed in a watch-and-wait strategy (59). However, based on several considerations, immediate treatment is crucial to allow proper development and maturation of NMJs, which occurs before two years of age. In mice, conditional depletion of Smn before postnatal day 17 caused SMA, while after that time, no phenotype was observed (88). Therefore, even if the therapy is discontinued or reduced, enough SMN should be available during the critical period of NMJ development and maturation. The amount of SMN might be insufficient in individuals with four SMN2 copies, as some patients with four copies developed SMA as early as eight months of age (175). Onasemnogene abeparvovec is approved only for children under two years of age in order to allow proper blood–brain barrier penetration of scAAV9-SMN1, and individuals with four SMN2 copies will also significantly benefit, since they most likely will never develop SMA under therapy. New Emerging Phenotypes With two approved drugs (nusinersen and onasemnogene abeparvovec) and others in the pipeline (risdiplam), one can envisage that almost every infant will be treated presymptomatically as soon as a homozygous SMN1 deletion is detected during newborn screening. However, even in countries where an SMA newborn screening has been implemented, there are still gaps in the health-care system (home birth, clinical capacity, infrastructure, and drug availability) that might prevent immediate treatment in the neonatal period, before the irreversible loss of motor neurons and the development of the first symptoms. Moreover, while it is very likely that individuals with three or four SMN2 copies will never develop any phenotype if treated presymptomatically, it is still questionable whether treatment of patients with two SMN2 copies will be sufficient to maintain the
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