Two research projects focused on developing gene-editing therapies for Charcot-Marie-Tooth disease type 2 (CMT2) – both launched with seed funding from the Association Charcot-Marie-Tooth-Research Acceleration Strategy (CMTA-STAR) program – have now received 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 projects for which it provided seed funding are now eligible to obtain funding from other entities.
Researchers Bruce Conklin, MD, and Luke Judge, MD, PhD, from the University of California, San Francisco, used the $653,000 seed funding awarded by CMTA-STAR in 2020 to develop techniques for editing CRISPR genes — a process by which gene mutations can be changed — for CMT2A, 2E and 2F.
These CMT2 subtypes are caused by different mutations that can, in principle, be corrected by gene editing, according to the CMTA.
CMT2A is caused by mutations in the MFN2 gene, which codes for the protein mitofin 2 – a protein involved in the fusion of mitochondria, the energy-producing structures in cells. In turn, CMT2E is caused by mutations in the NEFL uncomfortable. This gene provides the necessary 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 the beta-1 heat shock protein that helps neurofilaments maintain the diameter of axons – the long projections of nerve cells that transmit signals to the next nerve or muscle cell. Proper functioning of axons is an essential part of signal transmission.
Based on their work, Conklin and Judge have now received additional funding from the NIH. Researchers seek to develop and validate a gene-editing therapeutic platform for CMT2E mutations – mutations in NEFL— using models based on induced human pluripotent stem cells or iPSCs. These cells have been reprogrammed into an embryonic-like state that allows the development of any type of human cell, including motor neurons.
Using the iPSC-derived motor neurons will allow researchers to test mutation-specific gene editing for two different NEFL mutations and develop tests to assess the therapeutic effects of the technique.
In addition, the two researchers plan to identify sites of common genetic variation that can be targeted and used to inactivate dominant disease-causing mutations in the majority of patients. Dominant here means that only one mutated gene is needed for the disease state, rather than both, 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 can 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 of Ohio State University. This team received $265,000 in seed funding from the CMTA-STAR program, also in 2020, for the development of gene therapies to restore 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 the treatment of dominant CMT2E, according to the CMTA.
The CMTA has invested more than $17.5 million in the STAR program since 2008 and plans to fund an additional $10 million in CMT research over the next few years.