From Clinical Trials to Clinical Practice: Practical Considerations for Gene Replacement Therapy in SMA Type 1
Abstract Spinal muscular atrophy (SMA) is a devastating neurodegenerative autosomal recessive disease that results from survival motor neuron 1 ( SMN1 ) gene mutation or deletion. Patients with SMA type 1 (SMA1) utilizing supportive care, which focuses on symptom management, never sit unassisted, and 75% die or require permanent ventilation by 13.6 months of age. AVXS-101 (Zolgensma®) is a gene replacement therapy (GRT) comprising an adeno-associated viral (AAV) vector containing the human SMN gene under control of the chicken beta-actin promoter. It addresses the genetic root cause of the disease by increasing functional SMN protein in motor neurons and preventing neuronal cell death, resulting in improved neuronal and muscular function as previously demonstrated in transgenic animal models. In an open-label, 1-arm, dose-escalation phase 1 trial, systemic administration of AVXS-101 via a 1-time infusion over 1 hour demonstrated improved motor function and survival in all symptomatic SMA1 infants. Of the 12 patients who received the proposed therapeutic dose, 11 achieved independent sitting, 2 achieved independent standing, and 2 are able to walk. Most of these 12 patients remained free of respiratory supportive care. The only treatment-related adverse event observed was transient asymptomatic transaminasemia that resolved with a short course of prednisolone treatment. This review discusses the biological rationale underlying GRT for SMA, describes the AVXS-101 clinical trial experience, and provides expert recommendations as a reference for the real-world use of AVXS-101 in clinical practice. As of May 24, 2019, the Food and Drug Administration approved Zolgensma® (onasemnogene abeparvovec-xioi), the first gene therapy approved to treat children less than two years of age with spinal muscular atrophy (SMA).