Gene therapy for spinal muscular atrophy
Medically reviewed by Natalie Katz, MD
Gene therapy is a one-time treatment strategy that’s been developed for spinal muscular atrophy (SMA), a rare genetic disorder characterized by progressive muscle weakness and atrophy. As a treatment option, it aims to correct or replace the mutated gene that causes SMA.
The disease mainly affects motor function, but often also causes speaking, swallowing, and breathing problems, along with other SMA symptoms.
What is SMA gene therapy?
Nearly all cases of SMA are caused by mutations in the gene SMN1, which provides instructions for making the SMN protein. This protein is necessary for the survival of motor neurons, the nerve cells that govern movement.
Mutations in SMN1 lead to too little SMN protein being produced, resulting in the progressive dysfunction and death of motor neurons, which ultimately gives rise to disease symptoms.
The overarching aim of gene therapy for SMA is to deliver a working copy of the SMN1 gene to motor neurons, particularly motor neurons, thus allowing these cells to produce enough SMN protein. As with other diseases, gene therapy in SMA is given as a one-time treatment.
Types of gene therapy
Zolgensma (onasemnogene abeparvovec-xioi) is the only gene therapy currently approved to treat SMA. Marketed by Novartis, it uses a harmless, lab-engineered version of adeno-associated virus serotype 9 (AAV9) to deliver its genetic payload to the body’s cells.
In the U.S., Zolgensma is authorized to treat patients up to age 2 with all types of SMA caused by mutations in the SMN1 gene. The therapy also is approved in other countries, though specific indications may vary. In the European Union, Zolgensma has conditional approval for treating some SMA patients.
Novartis is also developing an experimental gene therapy, known as OAV-101, which is in Phase 3 clinical testing. OAV-101 contains the same active agent as Zolgensma, but is administered via injection into the spinal canal rather than intravenously. The company is also investigating use of this therapy in individuals older than age 2.
How is gene therapy administered?
The only approved gene replacement therapy for SMA, Zolgensma is administered via intravenous (into-the-vein) infusion. It typically takes about an hour to complete. The therapy is dosed according to a patient’s body weight.
Starting the day before gene therapy treatment, and for at least one month afterward, patients are given a course of inflammation-suppressing medicines called corticosteroids. This is designed to reduce the risk of the immune system responding to the gene therapy like an infectious threat. The aim is to prevent inflammation that damages organs, particularly the liver. Once liver lab values have normalized and are stable, the patient can be weaned off corticosteroid treatment over the course of about 30 days.
Values of liver enzymes should be monitored for at least three months following treatment with Zolgensma. Levels of platelets — cell fragments involved in clotting — and troponin-I, a marker of heart muscle damage, also should be monitored in the months following treatment.
Benefits of gene therapy
Gene therapy is a therapeutic approach specifically designed to treat the underlying genetic cause of SMA and replace the missing protein.
Clinical trials with Zolgensma, in particular, have demonstrated that gene therapy can slow the progression of SMA, significantly decreasing the risk of death or needing ventilation to help with breathing. Treatment with Zolgensma also may help normalize motor development. Some children with severe forms of SMA who were treated with Zolgensma have reached milestones such as walking independently, altering the natural course of the disease.
As an SMA treatment, Zolgensma may improve the quality of life of patients and reduce the amount of treatments needed over an individual’s lifetime. Like other disease-modifying SMA treatments, gene therapy is generally effective at slowing disease progression, but its ability to reverse damage that has already happened is limited. As such, treatment outcomes are generally more favorable when gene therapy is given as early as possible, with the best results typically seen when the medication is given before the onset of symptoms.
Clinical trials evaluating the efficacy of Zolgensma focused exclusively on young children, so little is known about the benefits the gene therapy may offer for adolescents or adults with SMA. Because gene therapy generally cannot reverse damage, it is expected to have limited utility in older patients or those with more severe symptoms.
Cost of gene therapy
Zolgensma is one of the most expensive drugs in the world, with a U.S. list price of $2.1 million for the one-time treatment. Novartis allows payment for the therapy in installments of $425,000 per year over five years. As a one-time treatment, however, Zolgensma offers significant therapeutic benefits with the potential to reduce the lifetime costs associated with the disease.
Some health insurers cover Zolgensma, but some do not — and even among companies that do provide coverage, many have criteria about who qualifies for the drug that are more strict than regulatory approvals. These criteria can include limitations on age or whether patients show symptoms.
Novartis has a program called OneGene that offers support to families of patients prescribed Zolgensma. Among other services, OneGene includes its CopayAssist Program to help cover out-of-pocket costs of the gene therapy for patients who have commercial insurance.
Nonprofit organizations such as the PAN Foundation also may help families affected by SMA cover costs of gene therapy and other treatments. The foundation provides assistance in the amount of $3,800 per year.
SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about SMA gene therapy
Gene therapy can slow the progression of spinal muscular atrophy (SMA), but has limited ability to reverse damage already accrued. As such, treatment outcomes are typically more favorable when gene therapy is given as early as possible. Some babies with SMA who were given gene therapy, specifically Zolgensma, before they developed symptoms, have reported near-normal motor development, but children treated later commonly have delayed or limited motor development.
In people with spinal muscular atrophy (SMA), chronic pain tends to arise due to mobility issues and scoliosis, or a sideways curvature of the spine, which put stress on the body. Early treatment with gene therapy can prevent disease progression, helping to improve motor development and thereby reducing the risk of developing these painful complications.
Zolgensma and Itvisma, the two approved gene therapies for spinal muscular atrophy (SMA), have a U.S. list price of $2.5 million and $2.59 million, respectively. Novartis, the company that sells both therapies, offers a patient support program that provides one-on-one assistance to families of patients prescribed Zolgensma and Itvisma.
Apart from Zolgensma and Itvisma, there are other approved disease-modifying therapies for spinal muscular atrophy (SMA). These include Spinraza and Evrysdi. Other therapies are being investigated in clinical trials.
About 1 in every 50 people is a carrier for spinal muscular atrophy (SMA), meaning these individuals have one copy of the SMN1 gene that carries a disease-causing mutation. SMA will only develop if both copies of the SMN1 gene — one inherited from each biological parent — contain a disease-causing mutation. If two carriers have children, there’s a 25% chance the child will develop SMA, a 50% chance that the child would be a carrier like the parents, and a 25% chance that the child would neither have the disease nor be a carrier.
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