Two research projects focused on the development of gene-editing therapies for Charcot-Marie-Tooth disease type 2 (CMT2) – both started with seed funds from the Association Charcot-Marie-Tooth-Strategy to accelerate research (CMTA-STAR) program – have now received additional funding from the National Institutes of Health (NIH).
According to a CMTA Press release, these NIH grants are a “key component” of the STAR program, as projects for which it provided seed money are now eligible to leverage funds from other entities.
Researchers Bruce Conklin, MD, and Luke Judge, MD, PhD, at the University of California, San Francisco, used the $ 653,000 seed funding granted by CMTA-STAR in 2020 to develop editing techniques for CRISPR genes – a process by which 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 NPF2 gene, which codes for the protein mitofusin 2 – a protein involved in the fusion of mitochondria, the energy-producing structures within 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 heat shock protein beta-1 that helps neurofilaments maintain the diameter of axons – the long projections of nerve cells that transmit signals to the next nerve or muscle cell. The 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 therapeutic gene editing platform for CMT2E mutations – mutations in NEFL – using models based on human induced 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 the editing of mutation-specific genes for two NEFL mutations and to 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 seed funding of $ 265,000 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.
NIH is now funding researchers Brown and Arnold as they develop their neurofilament restoration project and establish proof-of-principle for 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.