Turning the tide in spinal muscular atrophy: A different respiratory course

Spinal muscular atrophy (SMA) is a severe progressive neuropathy that presents in childhood and has a cumulative incidence of all subtypes of 1 in 10 000 live births. SMA is defined by the absence of the survival motor neuron 1 (SMN1) gene that produces survival motor neuron protein, which is felt to be important in maintaining the integrity of motor neurons, though the specific mechanism of function has not yet been fully elucidated. There is a second “back‐ up” gene (SMN2) that is present in variable copies ranging from 1 to 6. However, the SMN2 gene only transcribes a full length and functional SMN protein about 10% of the time due to the presence of a sequence in the intron after exon 7 that can prevent inclusion of exon 7 and 8 in the SMN protein product. There is a rough positive correlation between the number of SMN2 copies and the SMA phenotype. The traditional phenotypic representation is of SMA‐1 with respiratory failure within the first year of life and no ability to sit upright unassisted, SMA‐2 with respiratory failure in the first decade of life, the ability to sit upright, but not to walk, and SMA‐3 with no respiratory failure and an ability to walk. Two other phenotypic categories have been described at both ends of the spectrum with SMA‐ 0 with respiratory failure at birth and then SMA‐4 with full ambulation and modest extremity weakness. Without respiratory support patients with SMA‐0 and SMA‐1 universally die of respiratory failure within the first months or 2 years of life, respectively. While the focus of the medical management of SMA has moved toward a multidisciplinary approach that has been well described, there have been a variety of different pharmacologic approaches to SMA that have been variably successful. There have been prior attempts at improving SMN protein transcription (hydroxyurea, valproic acid, and sodium 4‐phenylbutyrate), stabilization of the SMN protein (aminoglycoside and proteasome inhibitors), and more downstream neuroprotection (riluzole, gabapentin, and olesoxime) none of which have been successful enough to be used broadly. More recently, however, nusinersen (Spinraza; Biogen, Cambridge, MA) and risdiplam (F. Hoffmann‐La Roche, Basel, Switzerland) have demonstrated efficacy in specifically blocking the inhibitor in intron 7 that prevents transcription of exon 7. Nusinersen, administered intrathecally, was approved by the Food and Drug Administration for all subtypes of SMA in December, 2016. Risdiplam, administered intravenously, is currently in phase 3 trials in the United States and in Europe. AVXS‐101 is a single dose adeno‐associated virus type‐9 gene therapy product that has been administered intravenously in infants with SMA‐1. In 15 infants with SMA‐1 it dramatically altered the course of disease with increased survival, improved motor function, and improved attainment of motor milestones, with the most dramatic effects occurring with the earliest administration. Dr Al‐Zaidy et al report respiratory and other outcomes in a cohort of 12 patients who were part of the previous cohort and were dosed at a mean age of 3.4 months and followed for an additional 2 years. The outcomes were: (1) pulmonary support (ventilation ≥16 h/ d), (2) nutritional support, (3) swallow function, (4) hospitalization rate, and (5) motor function. At baseline 10 of 12 subjects did not require noninvasive ventilation (NIV), and during the study three of the 10 subjects required NIV. Though each of these subjects had early progression of disease indicating a more severe phenotype, none of the subjects requiring NIV reached the pulmonary outcome of greater than or equal to 16 hours. Of the three subjects who required invasive ventilation during an acute respiratory illness, all three were successfully extubated and returned to their previous level of NIV. Seven of 12 subjects were able to feed exclusively orally at baseline and six of the seven maintained that capacity at the end of the observation period. In addition initially eight of the 12 subjects were able at least take oral feedings for a portion of their nutrition, but by the end of the study 11 were able to. Ten of the 12 subjects were hospitalized at least once during the study with a mean length of stay was 6.7 days. A total of 83% of the subjects were hospitalized for less than 10% of the study time, which is twice the percent reported in the control population from the ENDEAR study of nusinersen. Finally, 11 of the 12 subjects attained full head control and in doing so eliminate one of the major concerns in patients with SMA‐1, maintaining the integrity of the upper airway. The natural history of SMA‐1 is well known with a life span that can extend into the second year in some patients. Aggressive interventions to support airway clearance and mechanical ventilation can extend life expectancy; however, the underlying neuropathy progresses and there is an inexorable loss of muscle function. AVXS‐101 directly overcomes the causal event in SMA, absence of SMN1 and inadequate production of SMN protein. In doing so the progressive loss of function is replaced by attainment of developmental milestones. Dr Al‐Zaidy et al have wonderfully shown a different natural history with not only substantially better respiratory outcomes, but a strengthening and improvement in muscle function that has been unheard of. It is gratifying to see a stabilization and arresting the loss