Gene Therapy for Axonal Neuropathies

By Grace Pavlath, PhD

I’ve written recently about gene therapy approaches in development for CMT1A, a form of CMT that affects the myelin sheath of nerves.  There is also robust research to develop gene therapies for axonal forms of CMT that directly effect the nerve cells (types 2 and 4).  A recent article by Morelli et al reviews the state of research in axonal neuropathies ; I’ve highlighted these efforts below.

Giant Axonal Neuropathy

The most advanced use of gene therapy for an inherited peripheral neuropathy is in giant axonal neuropathy (GAN), a very rare form of CMT.   A clinical trial is underway testing the safety and efficacy of using a benign virus  (AAV) to deliver a normal version of the GAN1 gene to patients.


Proof of concept studies for gene therapy have been carried out in laboratory models of CMT2D due to a mutation in GARS. GARS mutations lead to the expression of a mutant protein which is toxic to peripheral nerves.  One approach to treating CMT2D would be to target and eliminate the messenger RNA (mRNA) responsible for the production of the mutant protein.  This study used a gene therapy approach to eliminate the mutant GARS mRNA in two models of CMT2D and almost completely prevented the neuropathy in these models when treated at birth.  The effects persisted for at least one year. Delaying treatment until after disease onset in the models showed modest benefit and this effect decreased the longer treatment was delayed.

Other Axonal Forms of CMT

According to the review article by Morelli et al, specific criteria should be met before testing gene therapy approaches to treat axonal forms of CMT:

  • A good understanding of the genetics underlying the disease,
  • Validated animal models of the disease, and
  • Available patient data defining the natural history of disease progression

Other axonal forms of CMT- CMT2A, CMT2E, CMT2S, CMT4A, and CMT4J- are discussed to be good candidates for gene therapy based on these criteria. Indeed, Passage Bio recently announced in a press release they are developing a viral gene therapy for CMT2A patients.  Neurogene is in partnership with UT Southwestern to develop a viral gene therapy for CMT4J, for which they are currently enrolling patients to gather natural history data.

Early successes in any of these axonal neuropathies, no matter how rare, will be important in driving the gene therapy field forward for CMT as a whole.