Most kinds of CMT come from a problem in a single gene. Repairing that faulty gene to stop the damage is called gene therapy, and for more than 10 years researchers have been studying how this approach could help people with CMT.
Gene therapy does no good if it can’t safely reach the right cells without harming the body. In most types of CMT, those are the Schwann cells. Schwann cells wrap around the nerves in your arms and legs and work like insulation. In the axonal types of CMT, the target is the nerve cells themselves.
A recent review by CMTA-funded scientists, Alexia Kaviava, PhD, Xin Chen MD, PhD, and CMTA-STAR Advisory Board members Richard Finkel, MD, Steven Gray, PhD, and Kleopas Kleopa, MD, PhD, looked closely at the progress and challenges over the last 10 years of getting the right gene to the right place to treat CMT.
Delivering genes where they’re needed
There are two main ways to deliver gene therapy. The first, intravenous (IV) delivery, sends the therapy through a vein, and the blood delivers it to the rest of the body, including the peripheral nerves. The second method, called intrathecal (IT) delivery, injects the therapy into the fluid around the spinal cord, which gets moved along to the nerves via the spinal fluid.
Studies comparing the two methods showed IT delivery reached the same nerves as IV but needed much less medication to get there. Smaller doses tended to result in fewer side effects and a milder reaction from the immune system. IT delivery also skips most of the bloodstream, so it is less likely to affect other parts of the body, making it the most likely delivery route to be use for CMT treatments.
What research revealed for gene therapy in CMT
The review covers more than a decade of research in gene therapy delivery for CMT. Almost all of these results are preclinical, meaning they happened in animal models, not in people. Preclinical is the step right before a treatment goes to clinical trials in people.
CMT1X comes from a faulty gene called GJB1. When this gene doesn’t work, Schwann cells cannot make a protein called connexin 32, which results in the myelin breaking down. Researchers put a healthy copy of GJB1 into the spinal fluid of three different mouse models. In each one, movement improved and nerve damage was reduced, even if the treatment began after symptoms appeared. A later study tested higher doses and found the same benefits, both in how the mice moved and in blood markers that track nerve damage.
CMT4C is the most common recessive demyelinating type of CMT. Recessive means both copies of the gene must be faulty for the disease to appear. As with CMT1X, the damage hits the myelin. Researchers delivered a working copy of the SH3TC2 gene, and it improved the structure and function of the nerves, again both before and after symptoms started.
CMT1A is the most common type of all. People with CMT1A have an extra copy of a gene called PMP22, so their bodies make too much of that protein. Here the goal is not to add a gene, but to turn one down. Researchers used a tiny piece of genetic code, called a microRNA, designed to lower how much PMP22 the body makes. In mice, it brought PMP22 levels down and improved function.
A similar turn-it-down approach helped in a mouse model of CMT2D. It didn’t work as well when treatment started after the nerve damage was already there, highlighting the importance of treating early in CMT. For CMT2S, a gene-replacement approach improved function in mice. That work has since moved into an early human trials by Biogen.
Tested for other conditions but will it work for CMT?
Researchers have tested IT delivery in people, but for other nervous system diseases, not CMT (yet). CMTA is funding research to find out how the approach can work for CMT too.
According to the review, the strongest evidence that IT delivery will work for CMT comes from spinal muscular atrophy (SMA). At higher IV doses, some patients had side effects from the gene therapy. Researchers then tried a lower dose given IT into the spinal fluid. Two phase 3 trials supported this approach and in November 2025, the FDA approved an IT form of a gene therapy for people with SMA two years and older.
Researchers have tried IT delivery in other conditions too. In giant axonal neuropathy, 14 people received IT gene therapy with few serious side effects, and a standard movement test showed possible benefit at some doses. A trial in CLN7, a form of Batten disease, was well tolerated over more than two years.
After a decade of research, questions remain
Some big questions about gene therapy remain, according to the review authors. How long does the benefit last? Can a patient safely get a second dose? Which medicines given alongside the therapy work best? These are the questions the next round of trials is designed to answer.
CMTA-STAR is currently funding seven studies in gene therapy. Support this work to find a treatment for CMT with a donation.
