The CMTA-STAR Preclinical Toolbox provides a validated, human-relevant CMT2A in vitro assay developed in collaboration with ANANDA Devices and BrainXell. The assay is now available and in use for drug screening.
Preclinical modeling of Charcot-Marie-Tooth disease type 2A (CMT2A) has been constrained by a well-characterized limitation: available rodent models can take time to provide answers for therapeutic evaluation of new treatments, and only one or two treatments are tested at a time. The Charcot-Marie-Tooth Association (CMTA) has moved to address this directly by creating a powerful new in vitro assay.
In collaboration with ANANDA Devices and BrainXell, CMTA developed and validated a human iPSC-derived motor neuron assay for CMT2A, presented at the Society for Neuroscience Annual Meeting in November 2025. It can quickly evaluate several treatments and conditions in a single study and their effects on the cellular biology of the neurons that cause CMT2A. The assay is now available to researchers and biopharmaceutical partners through the CMTA’s Strategy To Accelerate Research (CMTA-STAR) Preclinical Toolbox.
What is the CMTA-STAR Preclinical Toolbox?
The CMTA-STAR Preclinical Toolbox is a comprehensive set of research resources designed to reduce the time, cost, and biological uncertainty associated with early-stage CMT drug development. It includes CMT patient-derived iPSC lines and controls, plus differentiated neurons and Schwann cell precursors. The Toolbox also includes animal models across several subtypes that mimic CMT physiology, which is important for validating therapies before moving to clinical trials.
The Toolbox is designed to give researchers access to human-relevant disease models without the overhead of generating and validating these resources themselves. By providing validated, standardized biological resources, CMTA-STAR derisks preclinical programs and accelerates the path from candidate identification to translational readiness.
The CMT2A assay: platform and model design
CMT2A is caused by mutations in MFN2, a mitochondrial membrane-anchored protein. Disruption of MFN2 function impairs mitochondrial dynamics and mobility, and this new assay allows direct visualization of these mobility changes. The MFN2 R364W variant, used in this study, is associated with one of the most severe CMT2A pathologies.
BrainXell generated iPSC-derived spinal motor neurons from two sources: a healthy control line and a CMT2A patient-derived line carrying the MFN2 R364W mutation, both drawn from the CMTA-STAR Preclinical Toolbox. Neurons were cultured in ANANDA Devices’ NeuroHTS platform, which physically separates soma from axonal projections, enabling independent assessment of each compartment. The platform supports automated quantification of morphological parameters, alongside mitochondrial mobility and morphology metrics across soma, neurite channel, and axonal compartments. These cellular characteristics are impaired in CMT2A. The platform can test the ability of therapies to improve these characteristics. Successful therapies can then be validated for their physiological effects in CMT animal models.
Findings
Statistically significant differences between CMT2A and wild-type neurons were confirmed for three parameters: reduced cell area, reduced percentage of mobile mitochondria, and increased cell number. The reduction in mitochondrial mobility is consistent with the established role of MFN2 variants in impairing axonal mitochondrial transport, a finding replicated across multiple independent studies, as detailed in the presentation at the Society for Neuroscience Annual Meeting.
Critically, the assay has already been deployed for drug screening in CMT2A, demonstrating its operational readiness as a therapeutic evaluation platform.
Katherine Forsey, PhD, CMTA Chief Research Officer
Availability and research utility
The CMT2A assay is available now through the CMTA-STAR Preclinical Toolbox. For researchers or sponsors with programs targeting CMT2A, whether through MFN2 modulation, mitochondrial dynamics, axonal transport, or upstream pathway intervention, this platform offers a human-relevant, reproducible system for evaluating candidate compounds prior to in vivo studies. The standardized culture conditions and image analysis pipeline support parallel and combination screening, reducing experimental variability and accelerating lead prioritization.
CMTA-STAR engages with academic laboratories, biopharmaceutical companies, and clinical-stage sponsors. Toolbox resources are available through a collaborative access model. To discuss accessing this CMT2A assay or other Preclinical Toolbox resources, contact Stephen Lin, PhD, Director of R&D Alliances, at steve@cmtausa.org.
