CMT1A is caused by a duplication of the PMP22 gene leading to overexpression of the PMP22 protein and failure of the Schwann cells to produce myelin (the insulation of the nerve) well.  Without proper myelination, the nerves don’t send signals quickly or strongly, leading to nerve failure and eventual loss of nerves over time.   A number of publications demonstrate that the increased levels of PMP22 leads to demyelination and nerve damage in CMT1A.  With this as the premise,  Dr. Kleopa’s project  aims to use  a viral- mediated gene therapy approach to reduce the amount of PMP22 protein.
Dr. Kleopa is 6 months into a 24 month project and his preliminary results are encouraging.   The goal of the work during the first 6 months was to find the best type of virus to target  and reduce the amount of PMP22.  Dr. Kleopa is using a viral vector called AAV to deliver the gene silencing tool.  A mouse model of CMT1A overexpressing the human version of PMP22, was injected with two types of AAV and levels of PMP22 were compared between them.  Initial results indicate that this approach resulted in lowering of PMP22 levels and will be used for the remainder of the project.
There are several benefits to this approach:
o   Reducing the levels of PMP22 gets at the genetic cause of the disease rather than only treating the symptoms.
o   A gene therapy approach has the possibility of being a one time treatment.
o   AAV viral vectors are being used in other diseases like Spinal Muscular Atrophy as an FDA approved delivery mechanism.  Therefore, this method has a higher chance of being approved.
o   The experimental mice have the human version of PMP22, so the silencing tool under development has a greater chance of translating to patients.
o   There is growing interest by industry partners to commercialize gene therapy approaches to treat CMT.
o   If this project meets all of the critical milestones, it could be ready for partnership with industry and talks with the FDA.
Next steps are of utter importance: optimizing the viral approach is foundational.  More work needs to be done to optimize the amount of gene silencing in Schwann cells. Once that work is complete, the therapeutic effect will be assessed in the experimental mice.
While we are optimistic that this approach has a potential to have a strong therapeutic effect, this is still in the beginning stages of the project; the next 18 months will be critical. We vow to keep you informed and to share the realistic expectations as the project evolves.