Research Projects Launched With CMTA Seed Money Win NIH Funds
Two research projects focused on developing gene-editing therapies for Charcot-Marie-Tooth disease type 2 (CMT2) — both launched with seed monies from the Charcot-Marie-Tooth Association-Strategy to Accelerate Research (CMTA-STAR) program — have now been awarded additional funding from the National Institutes of Health (NIH).
According to a CMTA press release, these NIH grants embody a “key component” of the STAR program, as the projects for which it provided seed monies are now eligible to obtain funds from other entities.
Researchers Bruce Conklin, MD, and Luke Judge, MD, PhD, from the University of California, San Francisco, have used the $653,000 in seed funding awarded by CMTA-STAR in 2020 to develop CRISPR gene-editing techniques — a process by which gene mutations can be modified — for CMT2A, 2E, and 2F.
These subtypes of CMT2 are caused by different mutations that can, in principle, be fixed through gene editing, according to the CMTA.
CMT2A is caused by mutations in the MFN2 gene, which codes for the mitofusin 2 protein — a protein involved in the fusion of mitochondria, the energy-producing structures within cells. In turn, CMT2E is caused by mutations in the NEFL gene. That gene provides the needed codes for a neurofilament light chain protein that helps form the structural framework determining the shape and size of nerve cells.
Finally, CMT2F is caused by a mutation in the HSPB1 gene, which codes for heat shock protein beta‐1 that helps neurofilaments maintain the diameter of axons — the long projections of nerve cells that conduct signals to the next nerve cell or muscle cell. The proper functioning of axons is an essential part of signal transmission.
Based on their work, Conklin and Judge have now been awarded additional funding by the NIH. The researchers are seeking to develop and validate a therapeutic gene-editing platform for CMT2E mutations — mutations in NEFL — using models based on human induced pluripotent stem cells or iPSC. Such cells have been reprogrammed back into an embryonic-like state that allows the development of any type of human cell, including motor neurons.
The use of the iPSC-derived motor neurons will allow the researchers to test mutation-specific gene editing for two different NEFL mutations and to develop assays to evaluate the therapeutic effects of the technique.
Further, the two researchers plan to identify sites of common genetic variation that can be targeted and used to inactivate the disease-causing dominant mutations in the majority of patients. Dominant here means that only one mutated gene is necessary for the disease state, rather than the two, or one each inherited from the biological mother and father.
According to the CMTA, these studies may provide proof of concept for an approach that may be used in other forms of CMT2.
The second project is led by Anthony Brown, PhD, Arthur Burghes, PhD, Kathrin Meyer, PhD, and W. David Arnold, MD, all from the Ohio State University. This team was awarded $265,000 in seed funding by the CMTA-STAR program, also in 2020, for the development of gene therapies for restoring neurofilaments in diseased neurons in mouse models of CMT2.
The NIH is now funding researchers Brown and Arnold as they further develop their neurofilament restoration project and establish proof-of-principle of a gene therapy strategy in a mouse model of recessive CMT2E. In this case, recessive means that two mutated genes are needed for the disease to occur.
This work could potentially inform the general therapeutic strategy for treating dominant CMT2E, according to the CMTA.
The CMTA has invested more than $17.5 million in the STAR program since 2008, and has plans to fund another $10 million in CMT research over the next few years.