By Grace Pavlath, PhD

By now you’ve likely heard that CMTRF is funding three genetic-based projects focused on therapy development for CMT1A:    DTx PharmaShift Pharma and  Cyprus Institute of Neurology and Genetics.  Funding multiple complementary approaches gives the greatest chance for success in developing a disease-modifying therapy to slow down, stop or even reverse the course of the disease.

The majority of people with CMT have the 1A subtype which is due to duplication of  the peripheral myelin protein 22 (PMP22) gene leading to excess PMP22 protein and breakdown of the myelin that surrounds peripheral nerves.  With time this loss of myelin causes nerve dysfunction and degeneration resulting in loss of sensation,  weakness and loss of muscle bulk.

RNA therapeutics such as ASO, siRNA and miRNA can alter gene expression in multiple diseases including neuromuscular diseases.  Proof of concept was published for the use of ASO technology in a mouse model of CMT1A in 2018, but the doses used in the study were too high to be used in humans.  Thus, additional work is needed to harness the full power of RNA therapeutics for CMT1A.

RNA therapeutics differ in multiple ways including efficiency of delivery into nerves, mechanism of action, length of time in the body before redosing is needed, and side effects. All of these factors contribute to how well an RNA therapeutic could alter expression of PMP22. One can’t predict ahead of time which will work the best so it is important to test multiple approaches.

Delivery of RNA therapeutics to the peripheral nervous system (PNS) is a major challenge for CMT due to the blood-nerve barrier which acts to protect the PNS, but also serves as a barrier for drug delivery.   With funding provided by the CMT Research Foundation, both DTx Pharma and Shift Pharma are testing ASOs but with different chemical composition in order to get more effective delivery to Schwann cells which express the increased PMP22 in CMT1A.    In addition, DTx Pharma is also testing the effectiveness of siRNA technology .  DTx Pharma uses proprietary technology to link fatty acids to the ASO or siRNA as a means to potentially improve delivery to Schwann cells.  Dr. Kleopa at the Cyprus Institute of Neurology and Genetics is testing a viral means of delivering miRNA to determine if greater efficiency in lowering PMP22 levels can be achieved this way.

Success in one or more of these projects will pave the way to testing these approaches in patients with CMT1A.  Given that Schwann cells have been notoriously difficult to target with RNA therapeutics to date, success in any of these three projects will also help lower the barriers to therapy development in other demyelinating forms of CMT.