From Clinical Trials to Clinical Practice: Practical Considerations for Gene Replacement Therapy in SMA Type 1

Pediatric Neurology
Samiah Al-Zaidy, Jerry R Mendell

Abstract

Spinal muscular atrophy is a devastating neurodegenerative autosomal recessive disease that results from survival of motor neuron 1 (SMN1) gene mutation or deletion. Patients with spinal muscular atrophy type 1 utilizing supportive care, which focuses on symptom management, never sit unassisted, and 75% die or require permanent ventilation by age 13.6 months. Onasemnogene abeparvovec (Zolgensma, formerly AVXS-101) is a gene replacement therapy comprising an adeno-associated viral vector containing the human SMN gene under control of the chicken beta-actin promoter. This therapy 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, one-arm, dose-escalation phase 1 trial, systemic administration of onasemnogene abeparvovec via a one-time infusion over one hour demonstrated improved motor function and survival in all infants symptomatic for spinal muscular atrophy type 1. Of the 12 patients who received the proposed therapeutic dose, 11 achieved independent sitting, two achieved independent standing, and two are able to wal...Continue Reading

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