In more than 95% of patients with spinal muscular atrophy (SMA), the disease is caused by a deletion in exon 7 of the Survival Motor Neuron 1 (SMN1) gene located on chromosome 5q13.1,2,3  Because the etiology of most cases of SMA can be traced back to this single gene, the SMN1 gene has been an attractive target for gene therapy.

On May 24, 2019, the U.S. Food and Drug Administration (FDA) approved a one-time gene replacement therapy that successfully targets this gene. The drug, onasemnogene abeparvovec, is the first gene therapy that the FDA has approved for the treatment of SMA patients under the age of two. The drug is more commonly known by its trade name, Zolgensma, and was developed by AveXis (a company owned by Novartis) under the name AVXS-101.

Much of the initial clinical data on the impact of Zolgensma came from a Phase I clinical trial (NCT02122952) that included 15 patients who were homozygous for the SMN1 gene deletion with two normal copies of SMN2.4 The first three patients received one intravenous infusion of low dose onasemnogene abeparvovec (6.7 X 1013vg/kg) while the remaining 12 received 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.4 The average increase in the CHOP INTEND score was 9.8 points at one month and 15.4 points at 3 months. The historical cohort, by comparison, experienced declines in this score over the same time.

Despite participants being unexpected to sit due to their SMA type 1, 11 of the 12 children receiving the therapeutic dose were able to sit unassisted. In addition, nine rolled over, 11 could speak and could take food orally, and two children walked without assistance.4

Zolgensma treatment was associated with 56 serious adverse events and 241 non-serious adverse events.4 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, there is now ongoing research into the potential of Zolgensma to help SMA patients. For example, since 2017 the manufacturer has been conducting an open-label, single-dose pivotal trial called STR1VE, which is focused on symptomatic SMA patients less than 6 months old with one or two copies of the SMN2 gene. Both the Phase 1 results and preliminary results of phase 3 are promising.5,6

It is likely that a part of the success of Zolgensma is that it treats not only symptoms but also the underlying cause of SMA in the majority of patients. Specifically, it overcomes the negative effects of the genetic deletion by increasing functional SMN protein in motor neurons of SMA patients.

The therapy consists of an adeno-associated viral (AAV) vector that includes the human SMN gene that is under the control of the chicken beta-actin promotor. 7 The design of the AAV vector platform reduces the risk of the insertional mutagenesis that plagued early retroviral gene therapy trials. Its self-complementary AAV technology and its promoter allow for high and sustained human SMN expression by enhancing transgene translation and circumventing the rate-limiting step of synthesizing a second strand, which is usually required by recombinant AAV.

Another important element of the drug is its AAV9 serotype, which allows for the crossing of the blood-brain barrier. Research has also shown that when AAV9-SMN1 crosses the blood brain barrier, there is transgene expression in brain, spinal motor neurons, dorsal root ganglia, and glial cells throughout the central nervous system.8 The serotype therefore allows the drug to target the specific ells that are involved in the pathogenesis of SMA. Because motor neurons have a long lifespan, experts believe a one-time administration of this gene therapy should be sufficient for achieving transgene expression across the lifetime.

The FDA has classified Zolgensma as an orphan drug and given the product a Fast Track Designation and a Breakthrough Therapy Designation for SMA treatment. Zolgensma 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. 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

5. Mendell, JR, Shell R, Lehman, R. et al. Gene-Replacement Therapy in Spinal Muscular Atrophy Type 1: Long-Term Follow-Up From the Onsemnogene Abeparvovec-xioi Phase ½ Clinical Trial. Presented at the 2019 CureSMA Annual Conference; 2019.