Gene therapy for spinal muscular atrophy (SMA)

What is spinal muscular atrophy?

Spinal muscular atrophy (SMA) is a genetic disease that affects the spinal cord and nerves, resulting in muscle wasting and weakness. Untreated, it is a neurodegenerative, progressive disease, which can be fatal in its more severe forms. Children with the most common forms, type 1 and type 2 SMA, either never achieve sitting or can sit unassisted but will not be able to walk without genetically targeted treatment.

How is gene therapy used to treat spinal muscular atrophy?

Spinal muscular atrophy is caused by mutations in a gene called survival motor neuron 1 (or SMN1). In more than 95% of cases of SMA, the mutation is a deletion of a whole genetic segment called exon 7. Less commonly, the mutation is a spelling error (also called “point mutation”) or other genetic variants in SMN1.

There have been recent advancements in treating SMA with gene therapy. Gene therapy for SMA is called onasemnogene abeparvovec-xioi (brand name Zolgensma®).

Zolgensma delivers a new, working copy of a human SMN gene that is administered in a one-time infusion to children under 2 years old. Zolgensma makes up for the missing or nonworking SMN1 gene, which helps motor neurons work properly. The new gene tells motor neuron cells to produce more survival motor neuron (SMN) protein, which motor neuron cells need to survive and support muscle functions.

Narrator: Our team at Children's Hospital of Philadelphia wants to help you understand in vivo gene therapy. But before we can get into what in vivo means, we should start by explaining what is gene therapy? Gene therapy is a way to treat or prevent disease by using genetic material like DNA. First, the basics.
Our bodies are made up of cells. And inside each cell is its DNA. DNA is divided into short sections called genes. Genes act as instruction manuals, telling our cells how to make proteins. Proteins are necessary for our bodies to function. Proteins do important work like helping us digest food and helping our blood clot when we get a cut.
But sometimes, a gene's instructions for making a protein are not correct. This can cause changes in how a protein works. These incorrect instructions can result in a genetic disease. Gene therapy can deliver new instructions to the body to make proteins that function correctly.
Hannah: I was going blind. After I received a healthy gene to replace the bad gene in my eyes, I was able to see so much better.
Narrator: How does gene therapy work? There are two types of gene therapy. Ex vivo and in vivo. Ex vivo means outside the body. When a child receives ex vivo gene therapy, it means their cells are removed from their body, treated with gene therapy, and then put back into their body. In vivo means inside the body.
Let's talk more about how in vivo gene therapy works. When a child receives in vivo gene therapy, we use something called a vector, which acts like a delivery truck. Vectors with the new or corrected gene can get into the body through an iv, or doctors can put them in a specific spot, like the eye. The vector then travels to the cells where the corrected gene is needed.
With the help of the new gene, the cells start making the proper kind of protein. One condition that can be treated with an in vivo gene therapy, is spinal muscular atrophy, which is a nerve disease that used to be fatal for children with a severe type. Children with a disease now can receive an in vivo gene therapy that stops the progression of the condition.
William: Because of spinal muscular atrophy, I couldn't even roll over after gene therapy. I can now stand and take steps.
Narrator: Gene therapy is changing and saving children's lives and CHOP has been at the forefront of gene therapy breakthroughs from the start. CHOP was the first in the world to use in vivo gene therapy delivered into the bloodstream, which is the most commonly used method today.
And we've pioneered many other groundbreaking discoveries. Our determined researchers are exploring the use of in vivo gene therapy for all kinds of diseases so that more children worldwide will have bright futures.

Transcript Transcript

Spinal muscular atrophy treatment options at CHOP

Children’s Hospital of Philadelphia currently offers the one and only FDA-approved gene therapy for SMA: onasemnogene abeparvovec-xioi (brand name Zolgensma®). If your child is a candidate for SMA gene replacement therapy, we’ll walk you through the process, so that you know what to expect at every step. You can read more about the gene therapy process here.

CHOP also offers nusinersen (brand name Spinraza®) and risdiplam (brand name Evrysdia®) for the treatment of SMA in children and adults. Nusinersen and risdiplam are not gene therapy. Each is a medication that is used to increase production of the survival of motor neuron (SMN) protein, increasing the amount of functional protein produced from the SMN2 gene.

SMA is treated through our Division of Neurology, headed by Donna Stephenson, MD, and in collaboration with CHOP’s Neuromuscular treatment team.

Advocating for patients with spinal muscular atrophy

Research so far shows that the earlier children receive treatment, the better their outcomes. Once a motor neuron dies, the type of nerve cell affected in SMA, it’s gone forever. 

In July 2018, the U.S. Department of Health and Human Services approved SMA as an addition to the Recommended Uniform Screening Panel for newborns. CHOP neurologists Elizabeth Kichula, MD, PhD, and John Brandsema, MD, were on the committee that guided Pennsylvania through the complicated process of ensuring all newborns in the state were tested for SMA and referred promptly to appropriate treatment centers.

Because of their efforts, babies like Millie were able to be diagnosed within days of being born and treated quickly.

FDA approved gene therapy for spinal muscular atrophy

In May 2019, Zolgensma was approved by the FDA for treatment of children under age 2 years with all forms and types of SMA.

If your child is under 2 years of age and has genetically confirmed SMA, we will complete a clinical evaluation and additional testing to determine if they are a candidate to receive SMA gene therapy.

Additional clinical trials with Zolgensma are ongoing, including studies to see if it helps children older than 2. We encourage you to ask your child’s medical team any questions you may have, and we will share new information as it becomes available.

Clinical trials for spinal muscular atrophy

While the approved therapies for SMA are limited at this time, there are many medications currently being studied with the hope they may also become treatment options. CHOP has long been a site for research studies and clinical trials, continually seeking to find the next breakthrough in the treatment of SMA.

There are currently several active clinical trials for spinal muscular atrophy: