With CMTA support of $448,748, researchers are advancing CRISPR-based genetic therapies to address demyelinating forms of CMT, including CMT1A and CMT1B. In CMT1A, a duplication of the PMP22 gene leads to excessive PMP22 protein, damaging peripheral nerve myelin and disrupting Schwann cells, the specialized cells that produce and maintain peripheral nerve myelin. In CMT1B, dominant mutations in the MPZ gene impair Schwann cell function and destabilize peripheral nerve myelin.
The team, led by Bruce Conklin, MD (The Gladstone Institutes), Maurizio D’Antonio, PhD (Ospedale San Raffaele, Italy), and John Svaren, PhD (University of Wisconsin–Madison), is using CRISPR to develop precise gene-editing tools tailored to these distinct genetic mechanisms. For CMT1A, the goal is to inactivate the duplicated PMP22 gene copy while preserving the normal copy. For CMT1B, the strategy focuses on selectively targeting the harmful copy of the MPZ gene while leaving the healthy gene copy intact.
The Svaren and Conklin teams completed their portions of the CMT1A arm of this project in 2025. Dr. Svaren’s group mapped key regulatory regions of PMP22 that control its elevated expression in CMT1A, identifying specific sequences that can be targeted to reduce PMP22 levels. In parallel, Dr. Conklin’s team designed CRISPR tools capable of distinguishing and selectively targeting the extra PMP22 gene copy using shared DNA variations found in many patients. Together, this work established both the regulatory targets and the precision-editing framework needed for allele-specific correction of PMP22 duplication. Building on this foundation, the project’s CMT1B arm, led by Dr. D’Antonio, continues to test and refine CRISPR-based strategies targeting MPZ gene mutations in biologically relevant nerve tissue models.
February 2026 Update
While earlier therapeutic approaches, such as RNA interference and antisense oligonucleotides (ASOs), have shown potential, they also present challenges, including temporary effects and difficulty in selectively targeting the mutated gene copy. CRISPR-based approaches may overcome these limitations by enabling precise DNA-level correction.
Earlier in the project, Dr. D’Antonio’s team identified and screened CRISPR reagents (the molecular tools used to cut and edit DNA) in mouse models of CMT1B to determine which editing strategies showed the strongest activity against MPZ gene mutations. Building on that work, the team has now moved to laboratory-grown nerve tissue that includes Schwann cells and neurons. This allows them to study gene editing in a setting that closely mimics how peripheral nerves function.
The team is now testing these gene-editing tools in laboratory-grown nerve tissue from mice with CMT1B to see whether they can selectively turn off the harmful copy of the MPZ gene while leaving the healthy gene copy intact. Researchers are also evaluating whether this editing approach has measurable effects on peripheral nerve myelin, the protective covering around nerves that is damaged in CMT1B. These studies are designed to determine whether precise gene editing can function effectively in this biologically relevant nerve system.
Together, this work builds on prior screening efforts and represents an important step toward validating mutation-specific gene editing strategies in preclinical models of demyelinating CMT.
CMTA’s Strategy To Accelerate Research (CMTA-STAR) collaborative model supports collaborative efforts like this to address the underlying genetic causes of demyelinating CMT.
