Recommendations of gene therapy and disease-modifying therapies in children and adolescents with spinal muscular atrophy

Abstract

Spinal Muscular Atrophy (SMA) is a severe autosomal recessive neurological disease that affects 1-2 out of every 100,000 people and is classified into three types based on the age at the onset and motor milestones achieved. It is caused by pathogenic variants in the Survival of Motor Neuron 1 (SMN1) gene and modified by the number of copies of the SMN2 gene. There are three disease-modifying drugs approved by regulatory agencies: nusinersen, risdiplam, and onasemnogene abeparvovec.

Objective: To establish recommendations for the use of gene and disease-modifying therapy for SMA.

Method: A panel of 9 expert pediatric neurologists reviewed the available evidence and agreed on recommendations for the use of these drugs in patients with SMA.

Results: 21 studies were reviewed. All patients maintained the standard of respiratory and nutritional care. All three therapies were associated with improved motor, ventilatory, and survival prognosis compared to placebo or the natural history of the disease in presymptomatic patients (2-3 copies of SMN2), with SMA I (<6 months and without permanent mechanical ventilation (PMV), SMA II and III (without PMV). No high-quality studies were found demonstrating the efficacy of combination therapies, in advanced disease stages or with 0-1 copy of the SMN2 gene.

Conclusions: All three drugs are recommended for use in presymptomatic patients, with SMA I <6 months, SMA II, and SMA III, except in those with PMV, advanced stages, or 0-1 copies of SMN2. The use of these drugs in patients who do not meet these criteria must be evaluated individually by experts.