Onasemnogene abeparvovec gene-replacement therapy for spinal muscular atrophy: From bench to bedside

Introduction and objectives Spinal muscular atrophy (SMA) is a progressive neurologic disease that causes loss of motor and bulbar muscle function essential for normal breathing and swallowing. If untreated, SMA can lead to death/need for permanent ventilation by 2 years of age. The genetic root cause of SMA is lack of a functional survival motor neuron 1 (SMN1) gene. Here we describe the development of onasemnogene abeparvovec (formerly AVXS-101), a one-time intravenous (IV) SMN gene-replacement therapy (GRT) that treats the genetic root cause of SMA by delivering the SMN gene. Onasemnogene abeparvovec crosses the blood-brain barrier to target non-dividing motor neurons and is designed for immediate, sustained SMN expression. Methods SMA mice (Smn-/-) received IV scAAV9-SMN or scAAV9-GFP. Non-human primates (NHPs) received IV scAAV9-GFP and transduced cell types were assessed. In the first-in-human, open-label phase 1/2a study (NCT02122952), onasemnogene abeparvovec was administered as a one-time IV infusion at low (n=3) or therapeutic dose (n=12) in patients with SMA type 1 (SMA1); patients were followed for 2 years for safety/tolerability, survival (no death/permanent ventilation), motor milestones, and motor function. Patients could enroll in a long-term follow-up (LTFU) study that assesses safety. Results scAAV9-SMN improved survival and motor function in SMA mice. scAAV9-GFP targeted motor neurons in NHPs. In the phase 1/2a trial, all patients given the therapeutic dose survived event free to 24 months post-treatment; 11/12 patients reached CHOP INTEND ≥40 points (maximum: 60); 11 sat unassisted ≥5s, 9 for ≥30s; 2 crawled, stood, and walked. No previously attained milestone has been lost in LTFU; 2 patients have gained milestones. No patient received nusinersen during the 24-month study; 4 patients had asymptomatic transient rise in serum aminotransferase. As of 8 March 2019, the oldest patient was 4.8 years old (4.3 years post-treatment). Conclusions In the phase 1/2a study, onasemnogene abeparvovec GRT demonstrated unprecedented outcomes in symptomatic SMA1 infants compared with the untreated natural history of the disease. Long-term safety is being monitored for 15 years (LTFU). Global phase 3 trials in SMA1 are ongoing/planned. Additional trials are investigating the GRT in pre-symptomatic SMA and in older patients using intrathecal administration.