First Milestone Achieved
A Drug Screen for CMT2A
The CMT Research Foundation entered into a collaborative research partnership with AcuraStem to test thousands of compounds aimed at producing effective treatments for CMT2A. Using patient-derived stem cells, AcuraStem will screen nearly 3,000 drugs to measure their effect on CMT2A. The use of AcuraStem’s precision medicine iNeuroRx™ platform will drastically accelerate the pace of drug screening.
The partnership is milestone-driven and will be rolled out in phases, enabling the CMT Research Foundation to stop funding any research if it is deemed ineffective. Conversely, it also assures that if the studies produce a viable treatment that comes to market, the Foundation will benefit, enabling it to fund more promising research.
We believe that our iNeuroRX™platform could be the key in finding a transformative drug target for in this underserved population of individuals with CMT. We have made great strides in modeling ALS, and now we are excited to build on our early successes through our collaboration with the CMTRF. It’s a logical next step to extend our innovative, patient-focused platform to address CMT, another devastating, rare degenerative motor neuron disease.
Dr. Maurizio D’Antonio, I.R.C.C.S. Ospedale San Raffaele, Milan, Italy
Genetic Modulation of Unfolded Protein Response in CMT1B After Symptom Onset
The CMT Research Foundation has a collaborative research partnership with Dr. Maurizio D’Antonio who made several important discoveries in MPZ, including the identification of the UPR disease mechanism that can be modulated thanks to a compound named IFB-088. Currently in testing in a phase 1 clinical trial, IFB-088 could advance to a phase 2 clinical trial for CMT1B, sponsored by Inflectis BioScience.
This project will test the genetic modulation of the same pathway in adult animal models with CMT1B to determine if treatment with the compound later in life may modify the course of the disease. If this genetic proof of principle is effective in animal models, the compound may be applicable to people who’ve suffered from symptoms of CMT1B for decades. Knowledge gained through this project could accelerate the advancement of clinical trials and possible approval of treatment for adults with CMT1B.
Dr. James Dahlman, Georgia Institute of Technology and Emory School of Medicine
Using Lipid Nanoparticles to Deliver CMT Therapies to the Peripheral Nervous System
This innovative research collaboration seeks to overcome the challenges of delivering CMT therapies to the peripheral nervous system by using lipid nanoparticles (LNPs), considered among the most advanced delivery systems for genetic therapies. Dr. James Dahlman is a world-renowned expert in the design of lipid nanoparticles and has developed a system to rapidly identify LNPs that can enter other cell types. Using this approach, he has designed nanoparticles that efficiently deliver gene therapy payloads outside the liver, and several have been licensed for clinical development.
With funding from the CMT Research Foundation, Dr. Dahlman and his research team will utilize this approach to identify LNPs that can deliver genetic therapies to Schwann cells — the specialized cells that protect the peripheral nerves and whose dysfunction causes disease in the most common forms of CMT. The Food and Drug Administration (FDA) and European Medical Association (EMA) have already approved LNPs to treat another genetic condition. Additionally, LNPs serve as the delivery vehicle for two of the COVID-19 vaccines that have received FDA emergency use authorization and are now being rolled out worldwide. However, LNPs have not yet been tried in CMT because of the difficulty in designing them to target tissues other than the liver.
If successful, findings from this study could ultimately result in the design of therapies for CMT patients that restore normal protein function.
Second Milestone Achieved
We are pleased to report that DTx Pharma has successfully completed the second milestone of the CMT1A project.
Optimizing RNA-based Therapeutics as
Gene Therapy for CMT1A
The CMT Research Foundation is collaborating with DTx Pharma to build on previous proof of concept work demonstrating that antisense oligonucleotides (ASO) can decrease the levels of PMP22 in the peripheral nervous system of mice. DTx Pharma’s proprietary technology has the potential to render RNA-based therapeutics, such as ASO and siRNA, more potent, safer and longer-acting and to move this technology closer to the clinic for CMT1A patients.
DTx Pharma has developed proprietary technology based on lipidation, the direct conjugation of long chain fatty acids to ASO or siRNA. Their technology could enable access of ASO and siRNA to cell types and drug targets that small molecules and biologics could never be able to modulate.
This partnership is milestone-driven and will be rolled out in phases, enabling the CMT Research Foundation to halt funding if it is deemed ineffective. Conversely, it also assures that if the studies produce a viable treatment that comes to market, the CMT Research Foundation will benefit, enabling it to fund more promising research.
Our technology is well-matched to the peripheral nervous system, but we hadn’t considered CMT as a target until meeting with the CMT Research Foundation. Partnering with the CMT Research Foundation provides DTx Pharma with scientific and clinical experts who specialize in peripheral neuropathy, while connecting with patients and families affected by CMT helps us understand the need to accelerate development of new therapies for CMT.
The Jackson Laboratory
Building Disease Models to Better Understand How Mutations in MPZ Lead to CMT1B
The Jackson Laboratory will create several mouse models that will be instrumental in learning how gene mutations in MPZ lead to degeneration of the myelin sheath surrounding nerves in CMT1B. This is an important project for CMT drug development because these models will add to the supply of “humanized” models in CMT, of which there are very few today. The models will be made to express the human form of the MPZ gene, which gives a higher probability of success for developing and testing gene therapies. Using these “humanized” models, the translation to people with CMT could be easier.
Second Milestone Achieved
Dr. Kleopas Kleopa, Cyprus Institute for Neurology and Genetics
A Genetic Therapy Approach to CMT1A
The CMT Research Foundation is partnering with the Cyprus Institute of Neurology and Genetics to study a gene therapy approach to lower levels of PMP22 protein, which is the protein coded for by the gene that causes CMT1A. Most recently, Dr. Kleopa and his team reported that their candidate therapy showed a substantial reduction in the PMP22 protein in the peripheral nerves of mice with CMT1A, along with improvements in nerve myelination and the ability of the nerves to conduct electrical impulses. Most importantly, the therapy improved strength and coordination in the mice.
After demonstrating tremendous progress, the CMT Research Foundation has extended funding for this project. The investment will support additional experiments to provide useful pre-clinical information needed for further development by biotech and pharmaceutical companies as well as potential clinical trials. If successful, this project could lead to the first genetic therapy for CMT1A.
We are excited to work on this project for the development of gene therapy for CMT1A. We hope this work will provide a clinically translatable approach to help patients. We thank the CMT Research Foundation for supporting our efforts and for their enthusiasm and commitment to expedite therapies for CMT patients worldwide.
Dr. Chris Lorson & Dr. Michael Garcia, University of Missouri
Precision Medicine Model for CMT
The CMT Research Foundation is collaborating with Dr. Chris Lorson and Dr. Michael Garcia of the University of Missouri to develop a precision medicine approach for CMT. Precision medicine is a medical model that considers the differences between individuals within a specific subgroup of patients to customize drug development and treatment strategies, instead of developing drugs for the “average patient” with a one‐drug‐fits‐all model.
In this research project, Drs. Lorson and Garcia will develop and test a new gene therapy approach that will both silence the abnormal gene and simultaneously replace it with genetic material that will produce normal protein. The research team will test this approach in an animal model of CMT2E that is already well understood, making it suitable for this proof-of-concept project. If the approach is successful, it could potentially be used for other forms of CMT and be a possible approach for many CMT-causing mutations that require both silencing of a mutated gene and replacement with normal protein — whether the mutation is currently known or has yet to be discovered. The ability to silence and replace genes, regardless of the specific mutation, is what makes this a precision medicine approach.
Dr. Rudolf Martini, University Hospital Würzburg
Inflammation as Potential Treatment Target for CMT1B
The CMT Research Foundation is collaborating with renowned nerve disease expert Dr. Rudolf Martini of University Hospital Würzburg to investigate whether inhibiting inflammation in the peripheral nerves could reduce symptoms and improve outcomes for patients with CMT1B.
CMT1B is not only associated with the loss of myelin, but also with the eventual destruction of axons. In recent years, research has implicated inflammation as a culprit in this axon dysfunction. This study will test whether inhibiting macrophage activation will prevent axon loss in an animal model of CMT1B. Macrophages are a type of white blood cells that appear to attack the myelin and axons in the peripheral nerves in some types of CMT1. While this process is not yet fully understood, the macrophages appear to be activated through a protein called colony stimulating factor 1, which is sensed by a receptor on macrophages, known as CSF1 receptor (CSF1R). Previous studies indicate that blocking, or inhibiting, CSF1R activity reduces axon damage in animal models of other CMT forms, such as CMTX. Now, research is needed to test whether macrophage inactivation through CSF1R inhibition will show similarly positive results in an animal model of CMT1B. If successful, this research will provide important proof of concept that preventing inflammation by blocking macrophage activation pathways is a potential treatment for people living with CMT1B.
A Novel Series of ASOs to Address CMT1A
Dr. Chris Lorson and the team at Shift Pharmaceuticals are testing a gene targeting approach to decrease the levels of PMP22 protein which is known to cause CMT1A. They are developing and analyzing a new series of morpholino-based antisense oligonucleotide drugs (ASOs). Work on Milestone 1 is underway to find the best route for delivering ASOs to laboratory models. These results will help shape future experiments. ASOs have been proven to silence the extra PMP22 protein, but getting them into the peripheral nerves at effective, yet non-toxic levels, has been a challenge. Our partnership with Shift Pharmaceuticals aims to safely deliver these gene silencing tools, in hopes of slowing, stopping or even reversing the symptoms of CMT1A.
Working with the CMT Research Foundation has felt like a partnership from day one. By leveraging Shift’s core technology and experience with therapeutic development with the CMTRF’s deep understanding of core science related to CMT (through their staff and extensive network of advisors), we have collaboratively created an excellent research plan to move molecules towards the clinic for CMT