Spinal Muscular Atrophy (SMA) is a genetic disease that impairs a person’s control over their muscles. It progressively weakens muscles, affecting the ability to move, swallow, and even breathe. A one-time gene therapy called Zolgensma has been developed to treat the underlying cause of this disorder.
The Genetic Basis of Spinal Muscular Atrophy
Spinal Muscular Atrophy is caused by a missing or mutated Survival Motor Neuron 1 (SMN1) gene. The primary role of the SMN1 gene is to produce SMN protein, which is necessary for the health of motor neurons. These specialized nerve cells in the spinal cord transmit signals from the brain to the muscles, enabling movement.
Without a sufficient supply of the SMN protein, motor neurons begin to degrade and die off. This loss disrupts the communication pathway between the brain and the body’s muscles. As a result, muscles weaken and atrophy, leading to the progressive physical impairments characteristic of SMA.
The severity of SMA varies, leading to its classification into different types. SMA Type 1 is the most severe, with symptoms appearing in early infancy, while other types have a later onset and slower progression. Since the irreversible loss of motor neurons begins shortly after birth, early diagnosis and intervention are important.
How Zolgensma Works as a Gene Therapy
Zolgensma (onasemnogene abeparvovec) is a gene replacement therapy that addresses the root cause of SMA. It works by delivering a functional copy of the human SMN1 gene to a patient’s cells. This process does not alter the patient’s original, faulty gene but provides a new version that enables the body to produce the missing SMN protein.
Zolgensma uses a modified, harmless virus called an adeno-associated virus serotype 9 (AAV9) as a transport vehicle, or vector. To prevent illness and an immune response, scientists remove the viral genes from the AAV9 vector. The functional SMN1 gene is then placed inside this empty vector to be carried into the target cells.
Once administered, the AAV9 vector travels through the bloodstream to target motor neurons. A major advantage of the AAV9 vector is its ability to cross the blood-brain barrier, a protective lining that prevents many substances from entering the central nervous system. This allows the therapy to reach motor neurons in the spinal cord. Inside the nucleus of these cells, the new gene forms a stable piece of DNA called an episome, enabling continuous production of the SMN protein.
Patient Eligibility and Administration
The U.S. Food and Drug Administration (FDA) has authorized Zolgensma for pediatric patients under two years old diagnosed with SMA from SMN1 gene mutations. The therapy is indicated across the spectrum of SMA types. This includes babies who have not yet shown symptoms but were identified through genetic screening.
A primary test checks for the presence of antibodies against the AAV9 vector. If a patient has high levels of these antibodies, their immune system may attack the vector, rendering the therapy ineffective. This screening is necessary to ensure the treatment is only given to individuals who can benefit.
Zolgensma is administered as a one-time intravenous (IV) infusion that takes about 60 minutes. To manage the body’s immune response to the viral vector, patients receive corticosteroids. This medication is given before and after the infusion to reduce the risk of an inflammatory reaction.
Outcomes and Potential Side Effects
Zolgensma has been shown to halt the progression of SMA and improve survival rates, especially for those with severe forms of the disease. Many treated children achieve developmental milestones that would otherwise be impossible, such as sitting without support, crawling, and walking. Early treatment, particularly before symptoms appear, is associated with the best long-term benefits.
Zolgensma carries risks, with the most serious being acute liver injury. The AAV9 vector can cause a significant inflammatory response in the liver. For this reason, patients’ liver function is monitored through regular blood tests for several months after the infusion.
Other potential side effects include thrombocytopenia, a low platelet count that affects blood clotting. Vomiting is also a commonly reported side effect following the infusion. These risks are managed alongside the benefits of halting a progressive disease.