Onasemnogene abeparvovec, sold under the brand name Zolgensma among others, is a gene therapy used to treat spinal muscular atrophy, a disease causing muscle function loss in children. It involves a one-time infusion of the medication into a vein. It works by providing a new copy of the survival of motor neuron (SMN) gene that produces the SMN protein. Spinal muscular atrophy stems from a mutation in the survival motor neuron 1 (SMN1) gene, causing survival of motor neuron protein deficiency vital for motor neuron survival. Onasemnogene abeparvovec, a biologic medication utilizing adeno-associated virus (AAV9) virus capsids containing an SMN1 transgene, is administered to motor neurons, boosting SMN protein levels. Common side effects include vomiting and elevated liver enzymes, while more severe reactions involve liver issues and low platelet count. Developed by AveXis and acquired by Novartis, onasemnogene abeparvovec gained various US Food and Drug Administration designations and approvals. Controversies included data manipulation concerns and delayed reporting to regulatory agencies. Onasemnogene abeparvovec's price is high, earning it the title of the world's most expensive medication at the time of commercial approval. This has later been exceeded by other gene therapies like etranacogene dezaparvovec. Several countries such as Japan, the Netherlands, Canada, Brazil and others negotiated a lower price for onasemnogene abeparvovec for their public healthcare systems.
Medical uses Onasemnogene abeparvovec was developed to treat spinal muscular atrophy, a disease linked to a mutation in the survival motor neuron 1 (SMN1) gene on chromosome 5q and diagnosed predominantly in young children that causes progressive loss of muscle function and frequently death. The medication is administered as an intravenous infusion. In the United States, onasemnogene abeparvovec is indicated for the treatment of children with spinal muscular atrophy with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. The active ingredient (drug substance) in Itvisma is identical to Zolgensma but formulated at a different concentration. Zolgensma is administered intravenously based on recipient weight to children aged less than two years of age with spinal muscular atrophy due to bi-allelic mutations in the SMN1 gene. Itvisma is a concentrated formulation in a smaller delivery volume, administered directly to the central nervous system via a single intrathecal injection independent of recipient weight, which expands treatment options available to people older than two years of age with spinal muscular atrophy. The treatment is approved in the United States and certain other countries for use in children with spinal muscular atrophy up to the age of two, including at the presymptomatic stage of the disease. In the European Union and Canada, it is indicated for the treatment of people with spinal muscular atrophy who either have a clinical diagnosis of spinal muscular atrophy type 1 or have up to three copies of the SMN2 gene. Spinal muscular atrophy is an autosomal-recessive neurodegenerative disorder caused by mutations in the SMN1 gene, characterized by irreversible and progressive motor neuron loss, leading to progressive muscle atrophy and weakness, and subsequent paralysis and death in the most severe cases. Spinal muscular atrophy has an incidence of approximately 4-10 per 10,000 live births.
Adverse effects Common adverse reactions may include nausea and elevated liver enzymes. Serious adverse reactions may include liver problems and low platelets. Transient elevated levels of cardiac troponin‑I were observed in clinical trials; the clinical importance of these findings is not known. However, cardiac toxicity was seen in studies of other animals.
Mechanism of action
SMA is a neuromuscular disorder caused by a mutation in the SMN1 gene, which leads to a decrease in SMN protein, a protein necessary for survival of motor neurons. Onasemnogene abeparvovec is a biologic medication consisting of AAV9 virus capsids that contains a SMN1 transgene along with synthetic promoters.
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