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Understanding How SMA Gene Therapy Works

Medically reviewed by Evelyn O. Berman, M.D.
Written by Brooke Dulka, Ph.D.
Updated on June 30, 2023

When a child is born with spinal muscular atrophy (SMA), a rare neuromuscular disorder, it’s the result of genes they inherited from both parents. Because SMA is driven by genetic factors, gene therapy has proved effective in treating SMA.

Gene therapy has the potential to change the lives of individuals with SMA, particularly if the treatment is given early. Read more about how gene therapy works and which gene therapies are available now for people with SMA.

Genetic Mutations Cause Spinal Muscular Atrophy

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, scoliosis (spine curvature), 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.

Read more about the genetics of SMA.

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 gene replacement therapy (replacing a mutant gene with a healthy one), “turning off” a gene that isn’t 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 Does Spinal Muscular Atrophy Gene Therapy Work?

SMA gene therapy targets one of the major genes associated with the disease, notably SMN1 and SMN2. The U.S. Food and Drug Administration (FDA) has approved three SMA gene therapy methods:

  • Nusinersen, sold under the brand name Spinraza
  • Risdiplam, sold under the brand name Evrysdi
  • Onasemnogene abeparvovec-xioi, sold under the brand name Zolgensma

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 replaces 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 by a health care professional at a hospital or clinic. After the initial four-dose treatment regimen, the drug 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 was approved 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 the drug increases blood levels of SMN protein in a manner similar 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, arthralgia (joint pain), 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 2. Zolgensma uses a viral vector and targets the SMN1 gene. This viral vector delivers a fully functional copy of the human SMN1 gene into the motor neuron cells.

Zolgenesma is a one-time intravenous treatment. This drug’s most common side effects are elevated liver enzymes and vomiting.

Outlook for Gene Therapy Methods in Spinal Muscular Atrophy

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 disease can be treated, and children with SMA are reaching developmental milestones seldom seen before treatment became available. Although gene therapy isn’t a cure, it’s a promising step in the right direction.

Building a Community

The social network mySMAteam is for people with spinal muscular atrophy and their caregivers. On mySMAteam, more than 2,200 members come together to ask questions, share advice and experiences, and make connections with people around the world who understand life with SMA.

Are you treating your child’s SMA with gene therapy? Do you have questions for others who have used gene therapy? Share your experience in the comments below, or start a conversation by posting on mySMAteam.

References
  1. Spinal Muscular Atrophy — The Lancet
  2. Spinal Muscular Atrophy (SMA) — The Muscular Dystrophy Association
  3. Gene Therapy for Spinal Muscular Atrophy: An Emerging Treatment Option for a Devastating Disease — Journal of Managed Care & Specialty Pharmacy
  4. Correlation Between SMA Type and SMN2 Copy Number Revisited: An Analysis of 625 Unrelated Spanish Patients and a Compilation of 2834 Reported Cases — Neuromuscular Disorders
  5. What Is Gene Therapy? — U.S. Food and Drug Administration
  6. Understanding How COVID-19 Vaccines Work — Centers for Disease Control and Prevention
  7. Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes — Pediatrics
  8. FDA Approves First Drug for Spinal Muscular Atrophy — U.S. Food and Drug Administration
  9. FDA Approves Oral Treatment for Spinal Muscular Atrophy — U.S. Food and Drug Administration
  10. FDA Approves Innovative Gene Therapy To Treat Pediatric Patients With Spinal Muscular Atrophy, a Rare Disease and Leading Genetic Cause of Infant Mortality — U.S. Food and Drug Administration
  11. Nusinersen Treatment of Spinal Muscular Atrophy: Current Knowledge and Existing Gaps — Developmental Medicine & Child Neurology
  12. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA) — Journal of Medical Chemistry
  13. Risdiplam Distributes and Increases SMN Protein in Both the Central Nervous System and Peripheral Organs — Pharmacology Research & Perspectives
  14. Biomarker Terminology: Speaking the Same Language — U.S. Food and Drug Administration
  15. Instructions for Use Evrysdi — Genentech
  16. Zolgensma — Cure SMA
  17. Spinal Muscular Atrophy (SMA) — Boston Children’s Hospital

Updated on June 30, 2023
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Evelyn O. Berman, M.D. is a neurology and pediatric specialist and treats disorders of the brain in children. Review provided by VeriMed Healthcare Network. Learn more about her here.
Brooke Dulka, Ph.D. is a freelance science writer and editor. She received her doctoral training in biological psychology at the University of Tennessee. Learn more about her here.

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