Spinal Muscular Atrophy (SMA) is a genetic disease that impacts motor neurons, nerve cells in the spinal cord responsible for controlling muscle movement. This leads to progressive muscle weakness and loss of muscle mass. Gene therapy has emerged as a significant advancement in SMA treatment, addressing the underlying genetic cause.
Understanding Spinal Muscular Atrophy
Spinal Muscular Atrophy is a genetic disorder stemming from a deficiency in the Survival Motor Neuron 1 (SMN1) gene. This gene provides instructions for producing the Survival Motor Neuron (SMN) protein. In individuals with SMA, mutations or deletions in the SMN1 gene lead to insufficient levels of functional SMN protein.
The SMN protein is necessary for the proper function and survival of motor neurons. Without enough of this protein, motor neurons in the spinal cord begin to shrink and die. This loss disrupts signals from the brain to the muscles, resulting in weakened voluntary muscles. The severity of SMA symptoms can vary, influenced by the number of copies of a neighboring gene, SMN2, which can produce a small amount of functional SMN protein.
How Gene Therapy Works to Address SMA
Gene therapy for SMA introduces a functional copy of the SMN1 gene into patient cells, addressing the genetic root cause and helping the body produce the necessary SMN protein. A primary example is onasemnogene abeparvovec (Zolgensma).
The new gene is delivered using a modified adeno-associated virus (AAV9) vector. This AAV9 vector is non-pathogenic and modified to carry the functional human SMN1 gene. It is chosen for its ability to cross the blood-brain barrier, allowing it to efficiently reach motor neuron cells in the central nervous system.
Once inside a motor neuron cell, the AAV9 vector releases the new SMN1 gene into the cell nucleus. This enables cells to produce the SMN protein, which is essential for maintaining healthy motor neurons. By restoring SMN protein production, Zolgensma can halt the progressive loss of motor neurons, potentially offering long-term benefits from a single treatment.
Administering the Therapy and Anticipated Outcomes
Gene therapy for SMA, such as onasemnogene abeparvovec (Zolgensma), is typically administered as a one-time intravenous infusion. The infusion usually takes about 60 minutes to complete. This therapy is approved for pediatric patients, generally those under two years of age with a confirmed genetic diagnosis of SMA.
Early intervention with gene therapy is considered beneficial, as it can help prevent further motor neuron degeneration before significant damage occurs. Children treated with Zolgensma have shown sustained improvements in motor function and have been able to achieve developmental milestones that would typically be impossible without treatment. For instance, some patients have gained the ability to sit independently, stand with assistance, or even walk.
Improvements in motor function can be measured by scales such as the Hammersmith Functional Motor Scale – Expanded (HFMSE) and the Revised Upper Limb Module (RULM). These assessments have shown increases in scores following treatment, indicating enhanced motor capabilities. Many patients experience improved survival rates and the ability to achieve various motor milestones.
Potential Side Effects and Patient Monitoring
While gene therapy for SMA offers significant benefits, it is associated with potential side effects that require careful management. One of the most common and serious side effects is liver toxicity, which can manifest as elevated liver enzyme levels and, in rare instances, acute liver injury or even liver failure. This risk is primarily due to the viral vector used to deliver the gene.
To mitigate the risk of liver complications, patients typically receive an oral corticosteroid before and after the Zolgensma infusion for at least 30 days. This prophylactic treatment helps reduce the immune response to the viral vector and protect the liver. Regular blood tests are performed to monitor liver function, including transaminase levels, for at least three months post-treatment.
Other reported side effects can include vomiting. Some patients may experience transient increases in troponin-I, a protein that indicates heart muscle damage. Thrombotic microangiopathy (TMA), a condition involving blood clots in small blood vessels, has also been reported and requires immediate medical attention. Ongoing monitoring by medical professionals is necessary to manage any adverse reactions and ensure patient safety.