Spinal muscular atrophy is a rare, neurological, genetic disease characterized by a mutation in the survival motor neuron 1 (SMN1) gene. Interestingly, the SMN2 gene is preserved in these patients. SMN1 and SMN2 code for the SMN protein. The SMN protein is critical for many functions within the motor neurons. The SMN protein helps in regulating cellular trafficking, cytoskeleton maintenance, and intracellular signaling. Mutations in the SMN1 gene lead to a lack of function SMN protein, which causes degradation of the alpha motor neurons in the CNS.1 These motor neurons help our body transmit signals from the central nervous system to all of the muscles we use for everyday functions. These muscles control our breathing, walking, talking, and even the simplest tasks like moving our toes. When patients with SMA have lack of the functional SMA protein, you see muscle weakness, respiratory insufficiency, and premature death.2 SMA occurs within every 1 in 11,000 births.4 Some clinical signs of SMA include soft or absent cry, lack of reflexes, belly breathing, hypotonia, and inability to eat. The most severe type of SMA, or infantile-onset spinal muscular atrophy, often presents within the first six months of life. About 50% of patients will die by the age of 10.5 months. Those who survive require more than 16 hours per day of ventilatory support. Without treatment, only 8% of patients survive free of respiratory support.1
Onasemnogene abeparvovec is an adeno-associated 9 (AAV9) vector based gene therapy. It is administered as a single intravenous infusion for the treatment of spinal muscular atrophy. This therapy uses an empty viral capsid to deliver a functional copy of SMN1 to the cell. The safety and efficacy of onasemnogene abeparvovec has been evaluated in the phase 1 START and the phase 3 STR1VE-US study. Both of these studies excluded patients who required nutritional and respiratory support. The STR1VE-EU study aimed to expand on the safety and efficacy parameters of onasemnogene abeparvovec in patients who require more support.4
In the STR1VE-EU study, all 32 patients received a dose of onasemnogene abeparvovec. The primary endpoint was the achievement of functional independent sitting for more than 10 seconds during any visit up to 18 months. 14 of 32 participants (44%) achieved the primary endpoint as compared to 0 patients in the PNCR matched natural history cohort. The secondary endpoint was ventilation free survival at 14 months. 31 of 32 patients achieved the secondary endpoint (97%) as compared to 6 of 23 (26%) of the natural history cohort patients. One patient in the study died from a hypoxic brain injury unrelated to the drug. The safety endpoints were similar to those that had been identified in the STR1VE-US and START studies. No new safety signals were identified. Overall, onasemnogene abeparvovec was proven to be safe and beneficial in patients with a more severe phenotype. This proves continued favor of the risk-benefit analysis in favor of onasemnogene abeparvovec. In patients with rare and devastating diseases, the chance of having a one-time treatment for patients is remarkable. This also leads to a lot of hope for the future of gene therapy.
Kolb SJ, Coffey CS, Yankey JW, et al. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017 Dec;82(6):883-891.
Singh RN, Howell MD, Ottesen EW, Singh NN. Diverse role of survival motor neuron protein. Biochim Biophys Acta Gene Regul Mech. 2017;1860(3):299-315.
Farrar MA, Park SB, Vucic S, Carey KA, Turner BJ, Gillingwater TH, Swoboda KJ, Kiernan MC. Emerging therapies and challenges in spinal muscular atrophy. Ann Neurol. 2017 Mar;81(3):355-368.
Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021 Apr;20(4):284-293.