Spinal muscular atrophy (SMA) is caused by a deletion in exon 7 of the Survival Motor Neuron 1 (SMN1) gene located on chromosome 5q13 In greater than 95% of patients.1,2,3  Since the etiology of most cases of SMA is tracked back to a single gene, the SMN1 gene has become an attractive target for gene therapy. AVXS-101 (AveXis, a company owned by Novartis) is the gene therapy product that has moved furthest through clinical development.

AVXS-101 is comprised of a human SMN transgene with an inverted terminal repeat (ITR) and a constitutive promotor housed in a capsid shell. The gene payload is contained in a recombinant, non-replicating adeno-associated virus (AAV) capsid. The AAV9 serotype was chosen because this type of AAV capsid freely crosses the blood-brain barrier. Indeed, studies in primates show AAV9-SMN1 crosses the blood brain barrier and results in transgene expression in brain, spinal motor neurons, dorsal root ganglia, and glial cells throughout the central nervous system.4 The capsid payload is a stable, full-length human SMN gene that forms a self-complementary, double-stranded molecule. This configuration circumvents the cell’s need to synthesize a second strand before transcription and protein synthesis. Lastly, the constitutive promoter delivers a relatively constant expression of the human transgene within target cells.

Much of what is known about the clinical effect of AVXS-101 comes a Phase I clinical trial (NCT02122952) that included 15 patients homozygous for the SMN1 gene deletion with two normal copies of SMN2.5 The first three patients received one intravenous infusion of low dose AVXS-101 (6.7 X 1013 vg/kg) while the remaining 12 received what will presumably be the therapeutic dose (2.0 X 1014 vg/kg). Fourteen of 15 patients received a 30-day treatment of prednisolone to suppress the immune response to be infused viral particles. 

At the end of the study period, all 15 patients survived compared to a historical population of SMA patents that had a survival rate of only 8%. In the high-dose (or therapeutic dose) group, patients experienced a rapid increase in the CHOP INTEND scale score from baseline.5 The average increase in the CHOP INTEND score was 9.8 points at one month and 15.4 at 3 months. The historical cohort, by comparison, experienced declines in this score over the same time. Even though participants had spinal muscular atrophy type 1 (generally expected to be non-sitters), 11 of the 12 children receiving the therapeutic dose were able to sit unassisted, nine rolled over, 11 could speak and could take food orally, and two children walked without assistance.5 

AVXS-101 treatment was associated with 56 serious adverse events and 241 non-serious adverse events.5 Two serious adverse events and three non-serious adverse events were treatment-related—all of which involved elevations in liver transaminases. These elevations could be suppressed with corticosteroid treatment.

Based on these promising results, additional clinical trials are planned. For example, the manufacturer is conducting an open-label, single-dose pivotal trial called STR1VE in at least 15 patients with SMA Type 1. This trial began enrolling in September 2017. In this trial, the cohort is comprised of symptomatic SMA patients less than 6 months old with one or two copies of the SMN2 gene. 

The FDA classified AVXS-101 as an orphan drug and gave the product a Fast Track Designation and a Breakthrough Therapy Designation for SMA treatment. AVXS-101 is also in the European Medicines Agency’s PRIority MEdicines (PRIME) program. These designations should help streamline the regulatory process during further development. 


1. Ogino S, Wilson RB. Spinal Muscular Atrophy: Molecular Genetics and Diagnostics. Expert Rev Mol Diagn. 2004;4(1):15-29. doi:10.1586/14737159.4.1.15 

2. Maretina MA, Zheleznyakova GY, Lanko KM, Egorova AA, Baranov VS, Kiselev AV. Molecular Factors Involved in Spinal Muscular Atrophy Pathways as Possible Disease-Modifying Candidates. Curr Genomics. 2018;19(5):339-355. doi:10.2174/1389202919666180101154916 

3. Wirth B. An Update of the Mutation Spectrum of the Survival Motor Neuron Gene (Smn1) in Autosomal Recessive Spinal Muscular Atrophy (Sma). Hum Mutat. 2000;15(3):228-237. doi:10.1002/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9 

4. Bevan AK, Duque S, Foust KD, et al. Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders. Mol Ther. 2011;19(11):1971-1980. doi:10.1038/mt.2011.157 

5. Mendell JR, Al-Zaidy S, Shell R, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1713-1722. doi:10.1056/NEJMoa1706198