Spinal muscular atrophy (SMA) is a severe childhood monogenic disease resulting from loss or dysfunction of the gene encoding survival motor neuron 1 (SMN1). The incidence of this disease is approximately 1 in 10,000 live births, with a carrier frequency of 1 in 54.1 SMA is characterized by the degeneration and loss of lower motor neurons, which leads to muscle atrophy. The disease is divided into four subtypes (1 through 4) on the basis of the age at onset and milestone achievement. SMA type 1 (SMA1) is the most severe form and most common genetic cause of death among infants.2 There are two forms of SMN; SMN1 is the primary gene responsible for functional production of SMN protein. SMN2 preferentially excludes exon 7 during splicing3 and, as a result, produces only a small fraction of functional SMN protein as compared with SMN1. Therefore, the SMN2 copy number modifies the disease phenotype, and the presence of two copies of SMN2 is associated with SMA1.3 Infants with SMN1 biallelic deletions and two copies of SMN2 have a 97% risk of SMA1.

Recent studies of the natural history of SMA1 (historical cohort) showed that the median age at symptom onset among infants with the disease was 1.2 months (range, 0 to 4 months), and the disease was characterized by hypotonia, severe weakness from early infancy, and failure to sit without support.4,5 In infants with SMA1 who have two copies of SMN2, the median age at death or the need for noninvasive ventilation for at least 16 hours per day for at least 14 consecutive days (considered equivalent to permanent ventilation) was 10.5 months.4 In one cohort of affected children, only 25% survived without permanent ventilatory support at 13.6 months, and 8% survived without this support by 20 months.4 Another prospective, multicenter historical study sponsored by the National Institutes of Health (NeuroNEXT)5 involving patients with two copies of SMN2 showed a median survival free of tracheostomy of 8 months (95% confidence interval, 6 to 17). All patients with SMA1 have a precipitous decline in respiratory and swallowing functions after birth and ultimately require mechanical nutritional support (through a nasogastric or gastrostomy tube) to maintain adequate nutrition and reduce the respiratory risks associated with aspiration. For patients with SMA1 in whom the onset of symptoms occurs by 3 months of age, most patients require feeding support by 12 months of age.4

Patients with SMA1 also do not achieve major milestones in motor function and have a decline in function, as measured on the CHOP INTEND (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale, which ranges from 0 to 64, with higher scores indicating better motor function, a tool that is sensitive to minor changes in motor function, such as antigravity movements of limbs.6-8 In a historical analysis of 34 patients with SMA1, all but 1 of the patients did not reach a score of at least 40 after 6 months of age.4 In the NeuroNEXT cohort, CHOP INTEND scores decreased by a mean of 10.7 points from 6 months to 12 months of age.5

Therapeutic strategies to increase levels of SMN protein in motor neurons have focused on enhancing the effectiveness of SMN2. One approach has been central nervous system delivery of nusinersen (Ionis Pharmaceuticals/Biogen), an antisense oligonucleotide that was developed to inhibit exon 7 splicing in SMN2. This drug has been shown to improve weakness in the murine model of severe SMA and to increase the median life span of affected mice from 16 days to 25 days.9,10 In December 2016, nusinersen was approved by the Food and Drug Administration for the treatment of SMA. This drug is administered by means of repeated intrathecal injections after four loading doses within the first 2 months of life.11

A potential alternative treatment for SMA1 is gene therapy, given as a one-time intravenous administration that delivers a copy of SMN in a self-complementary adeno-associated viral serotype 9 (scAAV9). (The coding region of this recombinant virus forms an intramolecular double-stranded DNA [or self-complementary] template.) This approach has induced SMN expression in motor neurons and peripheral tissues, which has countered the effects of SMA in a murine model and extended the average survival in this model from 15 days to 28.5 days with a low dose (6.7×1013 vg per kilogram of body weight) and to more than 250 days with higher doses of the vector (2.0×1014 and 3.3×1014 vg per kilogram).12-15

In addition to crossing the blood–brain barrier and targeting central nervous system neurons at all regions of the spinal cord,13 the systemic administration of AAV9-mediated gene therapy may be advantageous, given that SMN protein is ubiquitously expressed and SMA1 affects multiple systems (e.g., autonomic and enteric nervous systems, cardiovascular system, and pancreas16,17), along with many cell types (e.g., heart,18 pancreas,16,17 and skeletal muscle19). The self-complementary feature of the vector combined with a hybrid cytomegalovirus enhancer–chicken beta-actin promoter enables rapid and sustained expression of SMN. In April 2014, we initiated a study of gene-replacement therapy involving infants with SMA1 who received a one-time dose of scAAV9 with delivery of the human survival motor neuron gene (hSMN), under control of the chicken beta-actin promoter (scAAV9.CB.hSMN) (AVXS-101).