Gene Therapy for Spinal Muscular Atrophy (SMA): A Review of Current Challenges and Safety Considerations for Onasemnogene Abeparvovec (Zolgensma)

Abstract

Spinal Muscular Atrophy (SMA) is a genetic disease that causes weakness and wasting in the voluntary muscles of infants and children. SMA has been the leading inherited cause of infant death. More specifically, SMA is caused by the absence of the SMN1 gene. In May 2019, the Food and Drug Administration (FDA) approved onasemnogene abeparvovec, SMN1 gene replacement therapy, for all children with SMA younger than two years of age, without end-stage weakness. The objective of the study is to review the safety and efficacy of a novel gene therapy, onasemnogene abeparvovec (Zolgensma), for SMA and assess current challenges for gene therapy. For this, we have conducted a literature search on PubMed, MEDLINE, and Ovid (2019 to 2022) in the English language using the terms SMA, onasemnogene, and gene therapy. The search included articles, websites, and published papers from reputable health organizations, hospitals, and global organizations dedicated to bringing awareness to Spinal Muscular Atrophy. We found the first gene therapy for SMA to be onasemnogene, directly providing the survival motor neuron 1 (SMN1) gene to produce the survival motor neuron (SMN) protein. Onasemnogene is approved by the Food and Drug Administration and has the added benefit of being a one-time dose. On the downside, a major side effect of this treatment is hepatotoxicity. There is substantial evidence that the efficacy of therapy is increased when administered early to children under three months of age. Therefore, we concluded that onasemnogene appears to be an efficacious therapy for younger pediatric patients with SMA type 1. Drug cost and potential hepatotoxicity are major concerns. Long-term benefits and risks have not been determined, but it is more cost-effective and requires less time of treatment compared to the other used drug, nusinersen. Therefore, the combined safety, cost, and effectiveness of onasemnogene abeparvovec make it a reliable treatment option for treating SMA Type 1.

Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy

“…In human clinical trials and real-world settings, treatment-related severe adverse events have been reported in just over 10% of cases, with the most common being liver function abnormalities and fever. 92 109 118 Other important adverse event includes thrombocytopenia. It is essential to note that while most patients experience manageable adverse events, there have been reports of rare but severe adverse events.…”

AAV9-based PMM2 gene replacement augments PMM2 expression and improves glycosylation in primary fibroblasts of patients with phosphomannomutase 2 deficiency (PMM2-CDG)

“…Furthermore, we have chosen in this study the AAV9 serotype because of its documented ability to cross the blood-brain barrier, which has led to successful, non-invasive intravascular delivery in animal models of several diseases [ 16 , 17 ]. In fact, the Zolgensma® [ 14 ] gene therapy approved by FDA to treat Spinal Muscular Atropy (SMA), a neurological disease, also employed AAV9 as the delivery agent. Therefore, we are confident that the AAV9- PMM2 vector we designed and tested in this pilot study will allow us to further evaluate the efficacy of this modality in alleviating the neurological disease of PMM2-CDG in our ongoing studies.…”

Molecular Biomarkers for the Diagnosis, Prognosis, and Pharmacodynamics of Spinal Muscular Atrophy

“…However, the SMN2 copy number can be used in the choice of proper treatment. For example, onasemnogen abeparvovec is approved for the treatment of children with SMA type 1 and presymptomatic individuals carrying two or three copies of the SMN2 gene [107]. Recent reviews [37,108] concluded that SMN-related biomarkers (either mRNA-or protein-based) are unreliable predictors of disease severity.…”