Spinal muscular atrophy (SMA) is a genetic disease — a disease caused by a change, or mutation, in a person’s DNA. In SMA patients, there is a mutation in the SMN1 gene, which leads to a lack of SMN protein production, and ultimately to the loss of lower motor neurons. In humans, there is a second gene called the SMN2 gene, which is able to produce a small quantity of SMN protein. However this is not enough to maintain muscle function.

Researchers have been working on ways to increase the amount of SMN protein in the body of people with SMA. One approach is gene therapy, which researchers believe may be a way to treat the disease, either by correcting or replacing the faulty gene. This therapy involves an alteration in a person’s genes, either by replacing a defective gene or by adding a new one.

To introduce the genes into the cells, scientists have to use “carriers,” or vectors, that deliver the genes inside the cells. The vectors used in gene therapy are harmless viruses that “infect” the cells with the new DNA.

Scientists face an additional difficulty in SMN gene therapy: crossing the blood-brain barrier, which is needed to reach the cells in the spinal cord, the target of this therapy.

There are currently three large companies studying gene therapy approaches for the treatment of SMA.


AVXS-101 (Avexis) is the only gene therapy currently being tested in human clinical trials (NCT02122952). The compound received Orphan Drug status and Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of all types of SMA. The compound also received Fast Track designation for the treatment of SMA type 1.

This therapy has three main goals: delivering a fully functional copy of the SMN1 gene through a harmless vector into motor neuron cells; producing high enough levels of SMN protein to enhance motor function; and obtaining a rapid effect and a sustainable protein production.

Although the drug cannot reverse muscle loss that has already occurred, it is hoped that it can prevent further muscle degeneration caused by the lack of SMN protein.

The Phase 1 study is using two different drug concentrations to assess the safety and efficacy of intravenous delivery of AVXS-101 for the treatment of SMA type 1.


Genzyme (a Sanofi company) is currently conducting early stage research in SMA gene therapy that focuses on the delivery of the SMN1 gene into the cerebrospinal fluid using a harmless virus called AAV9 (adeno-associated virus 9). It has been previously proven that the delivery of AAVs carrying the SMN1 gene lead to improved survival in mice. A later study demonstrated a correlation between the levels of SMN expression and the effectiveness of the treatment. The study also showed that the reconstitution of SMN levels in the central nervous system (CNS) was enough to decrease the effects of the disease in the CNS and in the skeletal muscles.

Genethon Inserm

Researchers at Genethon Inserm in France have successfully conducted gene replacement therapy with AAVs in severely affected mice. The virus carrying the gene was introduced directly into the nervous system of the animals. Researchers analyzed the survival of the mice, the biological distribution of the virus, and the expression levels of SMN protein. They found that all treated mice showed a dose-dependant growth and had increased mean survival.

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