Spinal muscular atrophy (SMA) affects about one of every 10,000-11,000 children and it is the most common genetic cause of death in infancy. The disease causes hypotonia, progressive weakness, and loss of motor function; and patients with the most severe form (SMA Type 1) typically die due to respiratory failure by 6-10 months of age. Until recently, the only intervention available for these patients was supportive care. In almost all patients with the most severe form of SMA, the disease results from deletion of a specific gene, SMN1, that encodes spinal motor protein, which necessary for the survival of motor neurons. Humans have a second gene, SMN2, that also encodes this protein, but about 90% of the product of SMN2 product is unstable and cannot compensate for loss of SMN. Understanding of the molecular and genetic underpinnings of SMA has led to the development of new therapies that have been demonstrated to dramatically change the course of SMA. The first of these new interventions is gene therapy – replacement of the gene that is missing in the great majority of the patients with SMA. This approach has been shown to be very beneficial in a small group of infants with SMA Type 1. Results from infants who received gene transplants demonstrated survival far beyond that seen for untreated patients and achievement of motor milestones, including sitting, standing and walking. A second approach to treatment of patients with SMA is to correct the protein product encoded by SMN2. Three different agents, nusinersen, branaplam, and RG7916 have been developed to accomplish this. All three correct the messenger RNA encoding spinal motor protein, and all have been shown to increase SMN1 protein and to greatly increase survival and significantly improve motor function in patients with SMA Type 1. Nusinersen is an antisense oligonucleotide (a string of bases like RNA) that must be administered intrathecally (injected into the fluid surrounding the spinal cord) and both branaplam and RG7916 are administered orally. Results with all of these interventions have shown that early intervention provides better outcomes and strongly support the importance of newborn screening for SMA. While much remains to be learned about these new treatments, it is already clear that we have entered a new era in the treatment of this deadly disease.
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