Spinal muscular atrophy (SMA) is a genetic, neuromuscular disorder. Because SMA is mostly driven by genetic factors, rather than environmental, the potential use of gene therapy has been of great interest in the SMA medical community.

SMA is an autosomal recessive disorder. This means that a child needs to inherit a mutant copy of the gene from both parents to display the condition. In the case of SMA, this mutation is almost always a deletion of the survival motor neuron (SMN) 1 gene on chromosome 5.

This SMN1 gene normally provides the body with instructions to make the messenger RNA (mRNA) for SMN protein. Your body needs mRNA to make proteins. Without the proper genetic instructions to make SMN protein, cells in the spinal cord begin to break down. This breakdown leads to the symptoms of SMA, including worsening motor function, muscle weakness, spine curvature (scoliosis), and other progressive SMA symptoms.

Another gene related to SMN protein, SMN2, also plays a role in SMA. The more copies of the SMN2 gene a person has, the less severe their symptoms will likely be.

What Is Gene Therapy?

Gene therapy is any technique that changes someone’s genetic code in order to treat a disease. Gene therapy can include replacing a mutant gene with one that is healthy, “turning off” a gene that is not working right, or introducing a new or modified gene into the body.

These genetic therapies can be delivered in several ways, including using a modified version of a virus, called viral vector technology, which is sometimes used in vaccines.

How Can People With SMA Benefit From Gene Therapy?

Gene therapy has the potential to change the lives of individuals with SMA, particularly if the treatment is given early. People with SMA can benefit from gene therapy because SMA is a genetic disorder.

How Does SMA Gene Therapy Work?

SMA gene therapy works by targeting one of the major genes associated with the disease, notably SMN1 and SMN2. There are three SMA gene therapy methods currently approved by the U.S. Food and Drug Administration (FDA):

• Spinraza (nusinersen)
• Evrysdi (risdiplam)
• Zolgensma (onasemnogene abeparvovec-xioi)

Both Spinraza and Evrysdi target a process for cutting up genetic material, called gene splicing, at the SMN2 gene. Zolgensma is a replacement gene therapy that works by replacing an SMN1 gene that doesn’t work with a new, fully functional SMN1 gene.

Spinraza

The FDA approved Spinraza for use in December 2016. It can be used to treat all types of SMA. Spinraza is a piece of RNA genetic material that blocks the process that creates a dysfunctional SMA protein and allows the cells to make the functional SMN protein instead. By increasing the production of this normal SMN protein in the cell, it prevents the loss of cells in the central nervous system.

Spinraza is administered by injection into fluid surrounding the spinal cord. Injections are done at a hospital or clinic. After the initial four-dose treatment regimen, Spinraza is given every four months. The most common side effects found in the clinical trials on Spinraza were upper respiratory infection, lower respiratory infection, and constipation.

Evrysdi

Evrysdi is the newest gene therapy and the first FDA-approved oral drug to treat SMA. The FDA approved it for use in August 2020 for people with SMA types 1, 2, and 3. Similar to Spinraza, Evrysdi contains an SMN2-directed RNA splicing modifier and promotes the formation of functional SMN protein. However, this newer formulation has more widespread effects throughout the body than Spinraza.

Research in animals has shown that the levels of SMN protein in the blood may be a biomarker (a molecule that represents the effect of a disease or treatment) of Evrysdi function. This is because levels of SMN protein in the blood are increased by Evrysdi in a similar manner to other tissues and organs in the body, including the brain, heart, and spinal cord. This means that a blood draw might be used to monitor the effectiveness of Evrysdi for each individual with SMA.

This drug is given orally at home, once per day. The most common side effects of Evrysdi include fever, diarrhea, rash, ulcers of the mouth area, joint pain (arthralgia), and urinary tract infections.

Zolgensma

The FDA approved Zolgensma in May 2019 for use as gene therapy for all types of SMA in children under the age of two. Zolgensma uses a viral vector and targets the SMN1 gene. This viral vector is used to deliver a fully functional copy of the human SMN1 gene into the motor neuron cells.

Zolgenesma is a one-time, intravenous treatment. The most common side effects of Zolgensma are elevated liver enzymes and vomiting.

Outlook for Gene Therapy Methods in SMA

The future is promising for SMA gene therapy methods. Just a few years ago, there were no preventive treatments for SMA. Now, children with known genetic risks can be treated, and the harmful symptoms associated with SMA can be partially prevented or delayed. Although gene therapy isn’t a cure, it is a promising step in the right direction.

Building a Community

The social network mySMAteam is for people with spinal muscular atrophy. On mySMAteam, more than 1,400 members come together to ask questions, share advice and experiences, and make connections with people around the world who understand life with SMA.

Have you thought about gene therapy for SMA? Share your experience in the comments below, or start a conversation by posting on mySMAteam.