Pharmacological and clinical profile of Onasemnogene Aveparvovec, the first gene therapy for spinal muscular atrophy (SMA)

; formerly AVXS-101) is a one-time gene therapy designed to address the genetic root cause of spinal muscular atrophy (SMA) by replacing the function of the missing or nonworking SMN1 gene via an adeno-associated AAV9 viral vector. On March 19, 2020, the Japanese Ministry of Health, Labor and Welfare approved onasemnogene abeparvovec for the treatment of SMA patients <2 years of age, including presymptomatic patients with a genetic diagnosis. Patients must be negative for elevated anti-AAV9 antibodies. Onasemnogene abeparvovec is administered through a single intravenous infusion, delivering a new working copy of the SMN gene into a patient's cells. Intravenous administration of onasemnogene abeparvovec to SMA model mice resulted in sustained expression of survival motor neuron (SMN) protein, weight gain, improvement of motor function, and prolongation of survival. Its clinical efficacy and safety have been demonstrated through the Phase I START and Phase III STR1VE-US, STR1VE-EU, and SPR1NT trials, and their long-term extension studies. SMA and presymptomatic patients treated with onasemnogene abeparvovec have achieved rates of survival not observed in the natural history of SMA. Treatment has led to rapid motor function improvement, often within one month of dosing, and developmental milestone achievement, including the ability to sit without support. The most commonly observed adverse effects after treatment were elevated liver enzymes, which often resolved with a course of prednisolone, and vomiting. This review discusses the rationale underlying gene replacement therapy for SMA, and describes the basic science, clinical trial experience, and use of onasemnogene abeparvovec.