Autophagy Enhancers for CMT1A
In CMT1A the body produces too much PMP22 protein in the peripheral nerves, and a major goal of drug development in CMT1A is to reduce the amount of PMP22 protein in nerve cells. Samsara Therapeutics has discovered a number of drug-like molecules called autophagy enhancers that stimulate the body’s natural ability to remove and recycle damaged or dysfunctional proteins. In an early preclinical study, they showed that this class of drugs improves outcomes in CMT1A model mice, reducing PMP22 protein levels and restoring measures of nerve structure and function. This partnership will allow Samsara to further develop these molecules and prepare for clinical trials. The project is divided into two broad sets of activities – compound optimization and IND-enabling studies. If the project is successful, it will result in the identification of a lead candidate and a data package to submit to the FDA ahead of potential clinical trials. The principal investigator for the project is John K. Blackwood, PhD, Vice President of Biology (pictured).
HDAC6 Inhibitors for CMT1A
Histone deacetylase (HDAC) inhibitors are a class of drugs approved for various cancer indications that also hold promise in neurodegenerative disease. In particular, for CMT it is thought that HDAC inhibitors that are selective for HDAC6 (HDAC6 inhibitors) may provide a therapeutic effect through enhancing axonal transport and/or lowering PMP22 levels. Early attempts at this approach used HDAC6 inhibitors that relied on the presence of a hydroxamate group in the molecule. However, hydroxamate is now believed to be potentially toxic, causing genetic mutations in some cases. Spanish pharmaceutical company ORYZON has developed two drug candidate HDAC6 inhibitors with superior drug properties that do not rely on hydroxamate. This project will test these drug candidates in a mouse model of CMT1A, providing proof-of-concept evidence for further development of one or both candidates as a therapeutic for CMT1A.
Dr. Afrooz Rashnonejad, Ohio State University and Nationwide Children’s Hospital Center for Gene Therapy, Columbus, Ohio
Gene Therapy for All or Nearly All Forms of CMT1B
In CMT1B, the myelin sheath of the peripheral nervous system is compromised because of a dysfunctional protein created by mutations within a gene called, myelin protein zero, or MPZ (aka P0), a necessary component of the myelin sheath. With funding from the CMT research foundation, Dr. Rashnonejad is creating a gene therapy that has the potential to treat all or nearly all forms of CMT1B. The research team aims to design a gene therapy that both reduces the expression of the mutant MPZ and replaces it with healthy MPZ. Dr. Rashnonejad has already designed these elements of the gene therapy. The next step, made possible by your generosity, is to further develop them, package them together in an AAV9 delivery vector, and test the full therapeutic for safety and efficacy in CMT1B mouse models.
Dr. Charles Abrams, University of Illinois Chicago
Testing Inosine for Treatment of CMTX
The CMT Research Foundation is partnering with University of Illinois Chicago’s Dr. Charles Abrams to test a potential therapeutic for CMT1X, the second most common form of CMT, behind only CMT1A in prevalence. This project will test whether treatment with inosine may ameliorate CMT1X symptoms or even change the course of the disease. Inosine is an anti-inflammatory small molecule, and its levels are reduced in animal models of CMT1X. It is hypothesized that lower inosine levels may play a role in the nerve inflammation seen in people with CMT1X and that raising inosine levels may have therapeutic benefit. This project will test these ideas, and if successful, will culminate in a trial of inosine therapy in mice with a genetic mutation that causes CMT1X.
Dr. Alessandra Bolino, Ospedale San Raffaele, Milan, Italy
In Partnership with AcuraStem
Preventing CMT4B1 with a Novel PIKfyve Inhibitor
The CMT Research Foundation is collaborating with patient-based drug discovery platform company AcuraStem and renowned expert in CMT Dr. Alessandra Bolino to test a novel PIKfyve inhibitor for its ability to prevent disease in CMT4B1. This particularly severe form of CMT usually begins before a person’s third birthday, frequently leads to wheelchair use, and can even cause death from weakening of the muscles that control breathing.
CMT4B1 is caused by mutations of the gene MTMR2, which leads to excessive levels of a fatty substance called PI(3,5)P2. This in turn causes the myelin sheath to become misshapen and dysfunctional, quickly leading to nerve degeneration. Because this fatty substance is normally produced by the enzyme PIKfyve, inhibiting the activity of PIKfyve may lower PI(3,5)P2 levels to normal, thereby warding off nerve dysfunction and preventing the symptoms of disease. This two-year project will test the new PIKfyve inhibitor in both cell models and rodent models of CMT4B1.
This project has successfully passed its first stage, a series of tests to ensure that the drug candidate travels to the peripheral nerves in healthy animals and inhibits PIKfyve in the cells there. Furthermore, stage one resulted in finding a series of dose levels that are expected to be safe and effective in stage two of the research, a preclinical trial of the drug candidate in CMT4B1 mice.
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.
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.
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 “knockdown and replace” gene therapy for CMT2E, which is caused by mutations in the NEFL gene. This gene therapy is designed to both silence the abnormal gene and simultaneously replace it with genetic material that will produce functional protein. If the approach is successful, it could potentially be used for other forms of CMT as well, particularly those that are caused by 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.
Milestone 1 of the project is now complete, with encouraging results. In this stage of the research, the scientists tested several versions of the therapy for their ability to silence the NEFL gene, and three successfully reduced expression to nearly nothing. The team has now selected one version to take forward into testing in an animal model that has the human NEFL gene. Assuming success in that stage, the researchers will then design and test the full therapy, which will include a gene replacement portion in addition to the silencing portion.
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.
Dr. Kelly Langert, Loyola University Chicago Stritch School of Medicine and Edward Hines, Jr. VA Hospital
Targeted Delivery of Novel Therapeutics for CMT1X
The CMT Research Foundation In November 2021 awarded a grant to test a new therapeutic delivery system that may be capable of crossing the blood-nerve barrier and releasing its payload in the affected tissue without toxic side effects. Drug delivery is a fundamental problem in neurological diseases and frequently results in otherwise promising therapies failing to advance. Typically, the therapy cannot reach the nervous system or must be given in such high doses that it results in toxicity. In the peripheral nerves, this problem is caused in large part by the blood-nerve barrier, a structure that prevents many molecules from moving out of the blood stream and into nerve tissue. Overcoming this problem is significant. One way may be to package the treatment in such a way that it ‘tricks’ the peripheral nerves into allowing it entry across the blood-nerve barrier.
Kelly Langert, PhD who will be in charge of the project, is an assistant professor, Molecular Pharmacology and Neuroscience, Loyola University Chicago Stritch School of Medicine and the Research and Development Service of the Edward Hines Jr. Veterans Affairs Hospital. She will be joined in the project by her Stritch colleague, Associate Professor Virginie Mansuy-Aubert, PhD. Dr. Charles Abrams, neurologist and professor at the University of Illinois Chicago (UIC), one of the world’s foremost experts on CMT1X, and member of CMTRF’s Scientific Advisory Board, will serve as a collaborator and advisor.
“I am excited by the opportunity to test this new technology for application in CMT. Advances in nanomedicine and our understanding of the active role that immune cells like macrophages play in the nerve are allowing us to approach treatment of peripheral nerves in ways never before possible.”
We are pleased to report that AcuraStem has successfully completed the CMT2A project.
A Drug Screen for CMT2A
In this project, researchers at AcuraStem developed a new drug-screening platform utilizing cells donated by CMT2A patients. The team used this platform to screen several thousand compounds, many of them already approved by the FDA or international regulatory agencies for use in other diseases, for their ability to promote survival of CMT2A cells. In an initial screen, thirty-seven compounds were identified as being potentially therapeutic. The AcuraStem scientists then performed a more in-depth validation stage of the project, further narrowing down the compound list to eleven that may show therapeutic benefit for people with CMT2A. While more research is needed to follow up on these leads, this project has resulted in the development of important knowledge in the continuing effort to develop treatments and cures for CMT2A.
We are very pleased with the outcomes of this study. Using our iNeuroRx® technology platform, we successfully created patient-specific disease models using cells donated by patients with CMT2A. These patient models have the potential to be more predictive of benefit for CMT2A patients than traditional models. We then tested thousands of compounds to identify potential therapeutics in a fraction of the time it would have taken with traditional methods. More research is needed, but this study gives us important information to build from.
We are pleased to report that DTx Pharma has successfully completed the CMT1A project.
Optimizing RNA-based Therapeutics as
Gene Therapy for CMT1A
The CMT Research Foundation collaborated with DTx Pharma, Inc. (DTx) to design and test novel RNA-based compounds in an experimental model of CMT1A. This project was successful, and DTx is now in the ‘lead identification’ stage of developing a therapeutic candidate for the treatment of CMT1A. This means that scientists at DTx are making chemical and design optimizations to select the most promising version of the therapeutic candidate for further research and development. The next stage will be ‘IND-enabling’ research, which refers to a comprehensive suite of studies that are carried out in rodents and other model organisms to ensure the FDA and other regulatory bodies that the candidate therapeutic is ready for human clinical trials, which could begin as early as 2023.
This project built on previous proof-of-concept work demonstrating that antisense RNA therapeutics can decrease the levels of PMP22 in the peripheral nerves of mice. DTx’s proprietary delivery technology has the potential to render RNA-based therapeutics, such as antisense oligonucleotides (ASOs) and small interfering RNA (siRNA), more potent, safer and longer-acting.
The CMT Research Foundation introduced DTx Pharma to the CMT field and funded their first CMT research, with an initial investment of $128,000 for this project. DTx has leveraged successful results from this project to secure additional funding from the National Institutes of Health. Additionally, DTx recently raised $100M to take their pipeline of therapeutic candidates, including a therapeutic candidate for CMT1A, forward toward clinical trials.
At DTx, our entire team is deeply committed to the CMT1A program and to the patients for whom there is no current therapy. We are grateful to the CMT Research Foundation for its early funding of our program, as well as its ongoing commitment to opening doors for us with both patients and clinicians.
The researchers have successfully completed this CMT1A gene therapy project.
Dr. Kleopas Kleopa, Cyprus Institute for Neurology and Genetics, and Dr. Scott Q. Harper, Nationwide Children’s Hospital
A Genetic Therapy Approach to CMT1A
The CMT Research Foundation partnered with the Cyprus Institute of Neurology and Genetics and Nationwide Children’s Hospital to study a gene therapy approach to lower levels of PMP22, the protein whose overexpression causes CMT1A. The researchers showed that the therapy led to a substantial reduction in the PMP22 protein in the peripheral nerve tissues 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. The therapy provided these benefits whether the treatment was given at early or later stages of the neuropathy. Additional data from a project extension that funded a longer treatment period, an examination of the immune response to treatment, and an exploration of neurofilament light as a potential blood-based biomarker for the therapy also provided promising data.
Given the strength of these data, the asset is now in the process of being licensed by emerging biotechnology innovator Armatus Bio and will be known as ARM-101. This represents the second major success for the CMT Research Foundation. Just two and a half years after we began discussions about this project with Dr. Kleopa, the therapy is showing strong results consistent with a viable treatment for CMT1A and is now being adopted by industry to accelerate development for potential clinical trials.
ARM-101 is a promising therapeutic candidate with the potential to make a significant difference in many lives. These new data will enable us to attract investments to accelerate our development efforts, with the goal of reaching those who need it as soon as possible.
We are pleased to report that Shift Pharmaceuticals has successfully completed the CMT1A project.
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 (PMO ASOs). The key advantages of PMO ASOs are their low toxicity compared to other gene therapy approaches and their ability to target Schwann cells, the cells that produce myelin in the peripheral nerves.
In their CMT Research Foundation-funded studies, they first showed in cells that the PMO ASOs reliably reduced the expression of PMP22. They next took the most effective PMO ASO and tested it in mice genetically engineered to express too much PMP22 – “CMT1A mice” – with promising results. As expected, CMT1A had serious deficiencies in movement and balance, as measured by the fact that it took them much longer than healthy mice to traverse a fixed-length beam in a beam-walking task. However, treatment with Shift’s PMO ASO greatly reduced the traversal time to levels near those of healthy animals. Moreover, this effect held regardless of whether the CMT1A mice were treated within days of birth or treated closer to the age that symptoms first arise.
We are ecstatic to see how well our PMO ASOs work in CMT1A mice, and we appreciate that the CMT Research Foundation saw our potential early and decided to fund the work. We are committed to furthering this science and bringing our potential treatment closer to the patients who need it.”