Spinal muscular atrophy (SMA) is a debilitating disorder characterized by degeneration of large motor neurons. It is a heterogeneous group of disorders caused by a homozygous deletion in the survival motor neuron (SMN) gene on chromosome 5, resulting in a SMN protein deficiency. Small amounts of SMN protein are also produced by the SMN2 gene, which that differs from SMN1 by a single nucleotide. Spinal muscular atrophy types and phenotypic severity depend on the number of variations of the SMN2 gene and the amount of SMN2 protein produced. Because the SMN protein deficiency is the root cause of the disease, treatment strategies for SMA revolve around increasing SMN protein production. Nusinersen (Spinraza, Biogen, Cambridge, MA) was the only treatment option available for SMA until the FDA approved onasemnogene abeparvovec-xioi (Zolgensma, AveXis Inc, Bannockburn, IL), a one-time–administered adeno-associated viral vector–based gene therapy that delivers the SMN gene to the motor neuron cells. Data from clinical studies show significant improvement in motor milestone achievements and ventilator-free survival but are limited by approximately 5 years' worth of results. This one-time intravenous injection of this new gene therapy also bears a hefty price tag; however, it may be more cost effective in the long run versus the multiple intrathecal administrations needed with nusinersen. Drug access and use are hindered by drug cost, payer reimbursement issues, and lack of long-term data from clinical studies. Questions also remain regarding the safety and efficacy of repeated drug administration for patients with advanced disease.
Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype