Emerging treatments for hereditary demyelinating neuropathies

Abstract

Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous, progressive disorders without effective therapy. Several demyelinating CMT types result from cell-autonomous loss of function mechanisms specifically in myelinating Schwann cells. Therefore, we have developed cell-targeted gene replacement or gene silencing approaches to treat demyelinating CMT. Using clinically relevant adeno-associated viral (AAV9) vectors and lumbar intrathecal injection we achieved widespread vector biodistribution throughout the PNS. Delivery of the GJB1 gene encoding the gap junction protein connexin32 (Cx32), which is associated with X-linked CMT (CMT1X), resulted in restoration of Cx32 expression in Schwann cells. GJB1 gene replacement in a model of CMT1X provided phenotypic improvement in motor performance, nerve conduction velocities, and peripheral nerve morphology both at pre- as well as post-onset stages of the neuropathy. Likewise, replacement of the SH3TC2 gene associated with recessively inherited CMT4C neuropathy in a model of the disease resulted in improvement of functional and morphological abnormalities. Finally, a gene silencing approach was used to treat an overexpressing model of CMT1A, the commonest demyelinating CMT type caused by PMP22 gene duplication. AAV9-mediated delivery of PMP22-targeting microRNA resulted in efficient silencing of PMP22 expression in PNS tissues, along with improvement of functional and morphological abnormalities. Treatment-responsive blood biomarkers of CMT neuropathies were identified and validated across different disease models. Our studies provide proof of principle for the therapeutic potential of gene replacement or gene silencing to treat demyelinating inherited neuropathies.