What is the mechanism of action and use of Zolgensma (onasemnogene abeparvovec)?

From the Guidelines

Zolgensma (onasemnogene abeparvovec) is a gene therapy medication that works by delivering a functional copy of the human SMN1 gene to motor neuron cells, thereby enabling the production of the survival motor neuron (SMN) protein that is deficient in spinal muscular atrophy (SMA) patients. Its mechanism of action involves using a non-replicating adeno-associated virus vector (AAV9) to cross the blood-brain barrier and enter motor neurons, where the functional SMN1 gene is expressed 1. This therapy is used to treat SMA, a rare genetic neuromuscular disorder caused by mutations in the SMN1 gene. Some key points about Zolgensma include:

• It is administered as a one-time intravenous infusion at a dose of 1.1 × 10^14 vector genomes per kilogram of body weight, typically over about 60 minutes 1.
• It is approved for children under 2 years of age with SMA, with best results seen when administered before symptom onset or early in disease progression 1.
• The therapy helps prevent further motor neuron degeneration but cannot reverse damage that has already occurred, making early treatment crucial 1.
• Patients require liver function monitoring before and after treatment, as transaminase elevations are a common side effect 1.
• Corticosteroids are typically administered before and after infusion to manage potential immune responses to the viral vector 1. Zolgensma is one of the approved nucleic acid therapies, which also include other products such as Onpattro, Spinraza, and Luxturna, each with its own unique formulation strategy, such as chemical modification, covalent conjugation, encapsulation in lipid nanoparticles, or delivery using adeno-associated viral vectors 1.

From the FDA Drug Label

Onasemnogene abeparvovec is a recombinant AAV9-based gene therapy designed to deliver a copy of the gene encoding the human SMN protein. SMA is caused by a bi-allelic mutation in the SMN1 gene, which results in insufficient SMN protein expression Intravenous administration of ZOLGENSMA that results in cell transduction and expression of the SMN protein has been observed in two human case studies

The mechanism of action of Zolgensma (onasemnogene abeparvovec) is to deliver a copy of the gene encoding the human SMN protein to treat Spinal Muscular Atrophy (SMA), which is caused by a bi-allelic mutation in the SMN1 gene. The use of Zolgensma is for the treatment of SMA. 2 2

From the Research

Mechanism of Action

• Onasemnogene abeparvovec (Zolgensma) is a one-time gene therapy designed to address the genetic root cause of spinal muscular atrophy (SMA) by replacing the function of the missing or nonworking SMN1 gene via an adeno-associated AAV9 viral vector 3, 4.
• The therapy delivers a functional copy of the human survival motor neuron (SMN) gene to motor neuron cells, which produces SMN protein, responsible for the maintenance and function of motor neurons 4.
• The SMN protein deficiency is the root cause of SMA, and treatment strategies revolve around increasing SMN protein production 5.

Uses

• Onasemnogene abeparvovec is approved for the treatment of SMA patients <2 years of age, including presymptomatic patients with a genetic diagnosis 3, 6.
• The therapy has been shown to improve 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) 4.
• Onasemnogene abeparvovec has also been 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 4.
• The therapy is administered through a single intravenous infusion, and patients must be negative for elevated anti-AAV9 antibodies 3.

Adverse Effects

• The most commonly observed adverse effects after treatment were elevated liver enzymes, which often resolved with a course of prednisolone, and vomiting 3.
• Hepatotoxicity is a known risk that can generally be mitigated with prophylactic prednisolone 4, 7.
• Other potential adverse events include thrombotic microangiopathy, and recommendations for prednisolone tapering and monitoring are described 7.