With CMTA support of $248,950, researchers at the University of Texas Southwestern, led by CMTA’s Strategy To Accelerate Research (CMTA-STAR) Advisory Board member Steven Gray, PhD, and Xin Chen, MD, PhD, have advanced the development of a genetic therapy for CMT4A. This subtype of CMT is caused by loss-of-function mutations in the GDAP1 gene, which lead to progressive nerve damage, muscle weakness, and sensory loss.
The team has developed and tested an adeno-associated viral (AAV9) vector designed to deliver a healthy GDAP1 gene broadly across the nervous system in a CMT4A mouse model. A single intrathecal dose improved nerve conduction velocity and motor coordination, with treated mice showing meaningful gains in rotarod performance, beam walking, and overall movement. The therapy also partially corrected nerve pathology and appeared safe in long-term mouse studies, with no treatment-related safety concerns observed.
Additional analyses are underway to further validate these findings and explore the therapy’s impact on sciatic nerve structure. If results continue to support both safety and benefit, the team plans to pursue translational development.
December 2025 Update
Building on the earlier proof-of-concept findings in CMT4A mice, additional studies have confirmed that a single intrathecal dose of AAV9-GDAP1 improves peripheral nerve function and motor performance, and the team reports no evidence of treatment-related toxicity. These findings further support both the functional benefit and safety profile of GDAP1 gene replacement in this disease context.
To build on these results, the researchers are now testing the same gene therapy approach in additional animal models that more closely reflect the severity of disease seen in people. These studies examine both nerve structure and function to confirm that the treatment consistently and measurably improves nerve health. This additional work helps determine whether the therapy is likely to work reliably across different forms and severities of CMT linked to the GDAP1 gene, such as CMT2K.
Together, these data support continued progression along a translational development path consistent with prior CMTA-supported gene therapy efforts in GAN, CMT4J, and SPG50. This work also contributes to the development of a templated gene therapy strategy that may be adaptable to additional CMT subtypes.
CMTA’s Work Leads to NIH Grant for Gray and Chen
As a result of this CMTA-supported work, the National Institutes of Health (NIH) awarded a $456,500 two-year grant to Xin Chen, MD, PhD, and Steven Gray, PhD, in February 2026 to evaluate this therapy in rat models.
These studies will examine the efficacy and safety of the AAV9-GDAP1 gene therapy following lumbar intrathecal administration in newly developed rat models of GDAP1-related neuropathy provided by CMTA. The work will generate critical data on nerve structure and function to determine whether the therapy consistently improves peripheral nerve health.
If successful, these studies will provide key preclinical evidence supporting IND-enabling development and potential progression toward a first-in-human clinical program. The work may also help establish a broader proof of concept for gene replacement approaches that could be adapted to other forms of CMT linked to GDAP1, including CMT2K.
