In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy

Abstract

Until the recent development of disease-modifying therapeutics, spinal muscular atrophy (SMA) was considered a devastating neuromuscular disease with a poor prognosis for most affected individuals. Symptoms generally present during early childhood and manifest as muscle weakness and progressive paralysis, severely compromising the affected individual’s quality of life, independence, and lifespan. SMA is most commonly caused by the inheritance of homozygously deleted SMN1 alleles with retention of one or more copies of a paralog gene, SMN2, which inversely correlates with disease severity. The recent advent and use of genetically targeted therapies have transformed SMA into a prototype for monogenic disease treatment in the era of genetic medicine. Many SMA-affected individuals receiving these therapies achieve traditionally unobtainable motor milestones and survival rates as medicines drastically alter the natural progression of this disease. This review discusses historical SMA progression and underlying disease mechanisms, highlights advances made in therapeutic research, clinical trials, and FDA-approved medicines, and discusses possible second-generation and complementary medicines as well as optimal temporal intervention windows in order to optimize motor function and improve quality of life for all SMA-affected individuals.

Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA)

“…The SMA community has witnessed three recent breakthrough gene-targeted treatments for SMA patients: Spinraza (nusinersen), a SMN2-splicing antisense oligonucleotide approved by the US Food and Drug Administration (FDA) in 2016; Zolgensma (onasemnogene abeparvovec), an AAV9-mediated gene replacement therapy in 2019; and Evrysdi (risdiplam), a SMN2 splicing modifier small molecule in 2020 (see recent reviews by [ 43 , 44 , 45 ]). All of these three drugs significantly enhance the production of SMN protein levels and show remarkable efficacy in treating SMA patients.…”

Ethical Issues in Care and Treatment of Neuronal Ceroid Lipofuscinoses (NCL)–A Personal View

“…Infants with the SMA1 type mostly die within the first 2 years of life or require ventilation >16 h per day. Recently developed genetically targeted therapies drastically alter the rapid progression of the disease in the 1st years of life; the later course of disease remains uncertain (20) as longitudinal data are outstanding. Extraordinarily high costs (drug prices, personnel resources, etc.)…”

Matching-adjusted indirect treatment comparison of onasemnogene abeparvovec and nusinersen for the treatment of symptomatic patients with spinal muscular atrophy type 1

“…Four Phase II trials assessing safety and efficacy of risdiplam in different SMA types (1, 2, and 3) also reported positive results, including improvement in motor function [42]. More clinical research is needed to further assess and compare the shortand long-term efficacy and safety of risdiplam, nusinersen, and onasemnogene abeparvovec for SMA patients [43].…”