With CMTA support of over $160,000, an international team of researchers is developing genetic therapy approaches for CMT1A and other Schwann cell-related subtypes, such as CMT1B and CMTX1 (CMT1X, CMTX). In CMT1A, an extra copy of the PMP22 gene causes Schwann cells, specialized cells that produce and regulate peripheral nerve myelin, to make too much PMP22 protein. This overload damages myelin, leading to disease symptoms.
Led by John Svaren, PhD (University of Wisconsin-Madison), Stephen Gray, PhD (University of Texas Southwestern), and Kleopas Kleopa, MD (The Cyprus Institute of Neurology and Genetics), the team is creating therapies to silence the extra PMP22 gene copy. By restoring myelin production in Schwann cells to more normal levels, this approach could improve CMT1A symptoms.
The researchers tested custom genetic instructions to silence the PMP22 gene in cells before packaging them into adeno-associated viral (AAV) vectors. These vectors use a capsid, a simple protein shell, to protect the therapy and help it enter Schwann cells. Testing in a CMT1A mouse model identified a custom genetic instruction driven by a myelin protein zero (MPZ) promoter as the most effective. The MPZ promoter acts as an “on switch,” ensuring the therapy works only in Schwann cells.
While newer capsid variants showed promise, AAV9 remained the most effective for targeting Schwann cells. Combining the AAV9 capsid with the MPZ-driven therapy offers an encouraging path for treating CMT1A and may also serve as a model for CMT1B and CMTX1.
This collaboration is advancing targeted therapies that address the root causes of CMT1A by reducing PMP22 protein levels in Schwann cells. With encouraging results from preclinical studies, this project is paving the way for potential treatments that could transform the future for those living with CMT1A and other Schwann cell-related subtypes. Through its Strategy To Accelerate Research (CMTA-STAR) collaborative model, CMTA remains dedicated to driving innovative research and offering hope with breakthrough therapies.
