The Charcot-Marie Tooth Association today announced another $335,000 in grants to top CMT scientists leading the field in CMT Type 1 research. The grants represent the CMTA’s commitment to finding treatments and a cure for the CMT community and cover work on types 1A, 1B and other demyelinating forms of CMT, including type 4.

The Board of Directors approved the latest round of research grants and projects, each of which will have an impact on therapy development, from improving understanding of disease mechanisms to discovering new therapeutic targets and moving these into clinical trials, following careful review by the members of the CMTA’s Scientific and Therapy Expert Boards – 30 leading clinicians and scientists who are tasked with overseeing the peer-review process.

For more than three decades, the CMTA has funded basic, clinical and translational research aimed at unlocking the mechanisms of CMT. CMTA funding empowers scientists and clinicians working to develop safe and effective therapies capable of changing the lives of the 2.8 million people worldwide who live with CMT. The power of the CMTA’s Strategy to Accelerate Research, or STAR, comes from bringing top researchers together with pharmaceutical and biotechnology companies and patients to collaborate in the search for the breakthroughs that propel progress.

Schwann cell-targeted gene therapy approaches to treat CMT1A and other demyelinating neuropathies (Types 1 and 4)

Award Info: $154,000 Grant Awarded to Drs. Kleopas Kleopa, John Svaren and Steven Gray

Goals: Aim 1 – Engineer and test size-minimized promoters that can be used to control expression of the target gene being delivered to Schwann cells by an AAV virus, and Aim 2 – Examine the suitability of different AAV virus subtypes for their use in infecting Schwann cells and describe the ability of AAV subtypes to enter peripheral nerve in animal models.

Background: In order to optimize gene therapy approaches for the Type 1 demyelinating CMT neuropathies, there are important challenges to be overcome which include 1) The development of safe viral vectors (the gene “package” delivered by a virus to cells) and 2) the identification of viruses that can deliver a vector to peripheral nerve and enter Schwann cells with high efficiency.

In the case of CMT1A, the strategy going forward will ultimately be to silence the responsible gene that is overactive in Schwann cells.

For loss-of-function CMT types including CMT1X and CMT4, the approach will be involve replacement of the defective gene. Thus, development of promoters (the gene scaffold regulating expression of the genetic package) will require them to be small in size and to only work in Schwann cells. Short promoters would allow the packaging of several neuropathy-associated genes into the adeno-associated virus (AAV), which has a limited packaging capacity. It is presently not known which of the available AAV virus subtypes have the best distribution into peripheral nerve tissue, and can most efficiently enter Schwann cells. The proposed experiments will seek to enable a translatable gene therapy approach for CMT1A, CMT1X, and various CMT4 forms. This will also be the first testing of AAV9 virus distribution to Schwann cells in a larger animal model (primate).

The proposed experiments here, made possible through collaborations with leading experts (Drs. Kleopas Kleopa, John Svaren and Steven Gray) in their field of expertise, will maximize the potential for achieving a translatable gene therapy for CMT1A, CMT1X, and various CMT4 forms and leverages funded experiments from Dr Gray’s lab. In addition, the project will test four additional types of AAV developed by Dr. Gray that could work better for both CMT1A and CMT1X in delivering genes to Schwann cells, and two vectors will be tested for efficacy in a mouse model of CMT1A.

Mechanisms of axonal degeneration in late onset CMT1B neuropathy: molecular pathways and therapeutic approaches

Award Info: $180,000 grant awarded to Drs. Maurizio D’Antonio and Ghjuvan Shackleford

Goals: Aim 1 – To have a better understanding of the mechanisms that lead to pathology in a CMT1B late onset model (P0T124M), and Aim 2 – to identify and test new therapeutic strategies to counteract axonal degeneration.

Background: The development of the T124M model of late onset of CMT1B neuropathy was originally funded by the CMTA in the laboratory of Dr. Larry Wrabetz, and this project is a continuation of the original project.

Axonal degeneration is a common endpoint of peripheral neuropathies. Identification of molecules and mechanisms supporting axon survival is therefore critical.

The POT124M animal model (a late onset form) was generated and shows an axonal neuropathy caused by a mutation in Schwann cell P0. This model represents a significant step forward in the comprehension of CMT1B/CMT2J pathomechanism and to test new therapeutic strategies based on axonal protection by modulating of SARM1 pathway.

Moreover, the POT124M animal model provides an excellent paradigm to answer how myelinating glia provide axonal support independently of myelin. This project will identify signals and molecules that underlie glial support of axons, and could reveal new unifying therapeutic targets that are common to a large spectrum of neurodegenerative diseases.