Onasemnogene Abeparvovec: A Review in Spinal Muscular Atrophy

Abstract

Onasemnogene abeparvovec (Zolgensma ® ) is a gene therapy approved for the treatment of spinal muscular atrophy (SMA). Administered as a one-time intravenous infusion, onasemnogene abeparvovec uses the adeno-associated virus vector to deliver a functional copy of the human survival motor neuron (SMN) gene to motor neuron cells. SMN1 encodes survival motor neuron protein, which is responsible for the maintenance and function of motor neurons. In clinical trials, onasemnogene abeparvovec improved event-free survival, motor function and motor milestone outcomes in patients with SMA, with these improvements maintained over the longer term (up to a median of ≈ 5 years). Onasemnogene abeparvovec was also associated with rapid age-appropriate achievement of motor milestones and improvements in motor function in children with pre-symptomatic SMA, indicating the benefit of early treatment. Onasemnogene abeparvovec was generally well tolerated. Hepatotoxicity is a known risk that can generally be mitigated with prophylactic prednisolone. In conclusion, onasemnogene abeparvovec represents an important treatment option for patients with SMA, particularly when initiated early in the course of the disease. Plain Language SummarySpinal muscular atrophy (SMA) is a rare genetic condition that causes muscle weakness and wasting. Infants with SMA type 1, the most common form of the disease, are unable to sit without support and usually die before the age of 2 years if untreated. SMA is caused by a defect in the survival motor neuron 1 (SMN1) gene. This gene provides instructions for making survival motor neuron protein, which is essential for the health and normal function of the nerves that control muscles. Onasemnogene abeparvovec (Zolgensma ® ) is a gene therapy that replaces the missing SMN1 gene and is given as a one-time infusion into a vein. In patients with SMA, onasemnogene abeparvovec improved event-free survival (alive without breathing support), motor function and achievement of motor milestones. Patients maintained these improvements for up to ≈ 5 years after treatment. Onasemnogene abeparvovec also helped pre-symptomatic children reach motor milestones at ages similar to healthy children. Onasemnogene abeparvovec is generally well tolerated and is an important treatment option for patients with SMA, including those who are yet to develop symptoms.

Onasemnogene Abeparvovec: Post-infusion Efficacy and Safety in Patients With Spinal Muscular Atrophy (SMA)—A Fondazione Policlinico Gemelli IRCCS Experience

“…These values were then compared with the data reported in the drug registration study CL-303. 5 The 8 patients examined all had an established diagnosis of SMA 5q with a biallelic mutation in the SMN gene and a SMN gene copy number varying between 2 and 3.…”

Viral vector‐based cancer treatment and current clinical applications

“…125 Zolgensma is used for the treatment of spinal muscular atrophy (Type I). 126 Upstaza is utilized to treat an inherited disease with aromatic L-amino acid decarboxylase (AADC) deficiency. 127 Roctavian 128 and Hemgenix 129 are used to treat hemophilia A and hemophilia B, respectively.…”

“…Glybera was approved to treat lipoprotein lipase deficiency in 2012 124 ; Luxturna, based on AAV2, is used for the treatment of patients with biallelic RPE65 mutation‐associated retinal dystrophy 125 . Zolgensma is used for the treatment of spinal muscular atrophy (Type I) 126 . Upstaza is utilized to treat an inherited disease with aromatic L‐amino acid decarboxylase (AADC) deficiency 127 .…”

Novel chemical tyrosine functionalization of adeno-associated virus improves gene transfer efficiency in liver and retina

“…Owing to their non-pathogenic nature, low immunogenicity, ease of production, and the long-term persistence of transgene expression, recombinant adeno-associated viruses (rAAV) are one of the most widely used viral vector for in vivo gene therapy. Several rAAV-based gene therapy products (Luxturna, Zolgensma, Roctavian, Upstaza and Hemgenix) [9][10][11] have been approved in Europe and the United States. rAAVs thus constitute a promising platform for the treatment of many diseases.…”