The CMT Research Foundation is collaborating with Dr. Chris Lorson and Dr. Michael Garcia of the University of Missouri to develop a “knockdown and replace” gene therapy for CMT2E, which is caused by mutations in the NEFL gene. This gene therapy is designed to both silence the abnormal gene and simultaneously replace it with genetic material that will produce functional protein. If the approach is successful, it could potentially be used for other forms of CMT as well, particularly those that are caused by mutations that require both silencing of a mutated gene and replacement with normal protein — whether the mutation is currently known or has yet to be discovered. 

Milestone 1 of the project is now complete, with encouraging results. In this stage of the research, the scientists tested several versions of the therapy for their ability to silence the NEFL gene, and three successfully reduced expression to nearly nothing. The team has now selected one version to take forward into testing in an animal model that has the human NEFL gene.  

Milestone 2 has been completed, demonstrating successful incorporation of the optimal therapeutic candidate from stage 1 into a gene delivery vehicle. A healthy copy of the gene has also been built into the delivery vehicle in order to complete the “knockdown and replace” therapy. In this phase, the researchers also characterized a new mouse model of CMT2E which develops a more severe symptom profile earlier in life. This model will allow better measurements of the therapy’s success as the team moves into the final stage of the project.