Charcot-Marie-Tooth disease (CMT) is a common and debilitating disorder, affecting about 130,00 people in the United States and several million throughout the world and the X-linked form cased by mutations the GJB1 gene is the second most common. With the widespread availability of genetic testing, over 700 variants in GJB1 have been identified. However many of these are likely not disease causing. This leads to great difficulty with advising patients when results of genetic testing are obtained, because there is currently no way to reliably identify which of these variants are disease causing. This proposal aims to address that problem by studying a subset of these not characterized variants to allow us to develop an algorithm for determining pathogenicity of GJB1 variants.

https://doi.org/10.55762/pc.gr.157043

(Co-funded with CMT Research Foundation)

Charcot-Marie-Tooth (CMT) neuropathies are generally characterized by progressive muscular atrophy and weakness, with an age at onset usually comprised between the first and the second decade of life. Among CMT neuropathies, CMT4B1 is a very severe demyelinating neuropathy with childhood onset, characterized by myelin outfoldings, redundant loops of myelin in the nerve that degenerate causing axonal problems. This form of aberrant myelin is also a pathological feature of other forms of demyelinating CMT, such as CMT4B2, B3, CMT4C and CMT4H. Our laboratory demonstrated that loss of MTMR2 (Myotubularin-related 2) phosphatase is the cause of the disease. MTMR2 dephosphorylates phospholipids, important regulators of membrane trafficking, which is a key process in Schwann cells, the glial cells forming myelin in the peripheral nervous system. Our laboratory also generated in vitro and in vivo models of CMT4B1, which have been instrumental over the years to study the pathophysiology of this neuropathy. By investigating why loss of MTMR2 in Schwann cells provokes aberrant myelin, we identified a novel mechanism by which MTMR2 and its lipid substrate coordinate cytoskeleton dynamics and membrane growth within myelin-forming cells. In this project, we will further explore this mechanism of relevance in cell biology. We will also test whether pharmacological and/or genetic modulation of these pathways can represent an effective strategy for the therapy of CMT4B with aberrant myelin.

https://doi.org/10.55762/pc.gr.157015

Motor neuropathies (dHMNs) and ALS share common underlying mechanisms, including degeneration of peripheral nerves. Dysfunction at the junction between nerve and muscle, the neuromuscular junction (NMJ), is an early event contributing to motor neuron (MN) loss in dHMNs and ALS, with active denervation/reinnervation occurring during the disease. Importantly, the regeneration of nerves and muscles occurs also during adulthood to enable the repair of NMJs and damaged muscles; however, the regenerative abilities decline with aging, when these diseases develop. It is fundamental to better understand how dysfunctions of the neuromuscular system lead to dHMNs and ALS. This project aims to unravel players and mechanisms responsible for MN and NMJ vulnerability in dHMNs and ALS. We focus on the gene HSPB3, which is a promising candidate because: 1) rare HSPB3 variants have been found in dHMNs and ALS patients; 2) we have shown that HSPB3 is a specialized chaperone engaged in muscle and MN differentiation; 3) we found that HSPB3 induction is impaired in MNs carrying a mutation linked to ALS. We hypothesize that deregulation of the pro-differentiation functions of HSPB3 may contribute to NMJ deterioration with aging and in disease. Using human MNs and muscle cells and neuromuscular organoids derived from iPS cells we will study how HSPB3 dysfunction leads to degeneration and assess if its targeting increases the regenerative capacity of the neuromuscular system.

https://doi.org/10.55762/pc.gr.157046

One of the major challenges in developing therapeutics for inherited neuropathies is to achieve adequate access of drugs and gene therapy agents into the peripheral nerves throughout the body through a clinically applicable delivery route. The blood-nerve barrier (BNB) limits this distribution and the effectiveness of potential therapies. In order to overcome this, we propose to test an innovative method by transiently disrupting the BNB using a Focused-Ultrasound System (FUS). We will then test the efficacy of this method to facilitate penetration of viral vectors for gene therapy into peripheral nerves. As model disease, X-linked Charcot-Marie Tooth Disease (CMT1X) is a common inherited demyelinating neuropathy, characterized by progressive muscle atrophy, weakness and sensory loss in the limbs. CMT1X is caused by mutations affecting connexin32 (Cx32), a protein that is expressed specifically by myelinating cells in the nerves, the Schwann cells, and plays important role in nerve function and integrity. Using a previously developed gene therapy vector for treating CMT1X, we will examine the benefit of transient BNB disruption using FUS in order to maximize the gene delivery to Schwann cells and the therapeutic efficacy. Successful application of this technique can also benefit several other therapy approaches for inherited neuropathies as well.

https://doi.org/10.55762/pc.gr.157047

(Co-funded with the Charcot-Marie-Tooth Association)

X-linked Charcot-Marie Tooth Disease (CMT1X) is a common inherited neuropathy, characterized by progressive muscle atrophy, weakness and sensory loss in the limbs. CMT1X is caused by mutations affecting connexin32 (Cx32), a protein that is responsible for the formation of gap junction channels in the myelin sheath playing an important role in nerve function and integrity. We have already developed an effective gene therapy approach for treating CMT1X by delivering the gene encoding Cx32 by intrathecal injection to mice lacking the Cx32 gene using an AAV9 vector. The use of this vector resulted in widespread and long-lasting expression leading to pathological and functional improvement. Although AAV9 proved to be efficient, potential long-term toxicity and lack of cell specificity may limit clinical translation. In order to develop a safer and potentially more targeted approach we propose to design a novel aptamer-conjugated nanoparticle carrying the gene expressing Cx32 that would enable gene entry specifically to Schwann cells. We will then check its therapeutic benefit in a model of CMT1X neuropathy. This targeted nanoparticle approach may result in more targeted biodistribution and efficient gene expression providing a safer and more translatable novel approach for gene therapy to treat not only CMT1X but also other demyelinating neuropathies caused by gene defects in Schwann cells.

"Unraveling the cause of a human disease requires having appropriate animal models for the disease being studied. This proposal will characterize models for CMT1X on the molecular level and use them to initiate studies that will shed light on the causes of this disorder."

Charles Abrams, MD, PhD, professor of Neurology at the University of Illinois, Chicago, was awarded an MDA research grant totaling $300,000 over three years to better understand how mutations in the connexin 32 gene (Cx32) lead to CMT1X, a form of Charcot-Marie-Tooth disease (CMT).

Mutations in the gene coding for the gap junction beta-1 protein (GJB1), also known as connexin 32 protein (Cx32), are associated with the X-linked form of Charcot-Marie-Tooth disease (CMT1X), which affects approximately 1 in 25,000 people and is the second-most-common form of CMT. Although scientists have known about these mutations for more than 25 years, information is still lacking about how they cause disease. In the case of CMT1X, animal models are inadequate — almost all studies have used the Cx32 gene knockout mouse, a loss-of-function model that may not accurately represent the full spectrum of the variety of mutations in Cx32 that can cause CMT1X.

This work will use a technique called RNA-Seq to characterize a variety of different CMT1X mouse models at the level of transcription (RNA), and it will then utilize this information for studies into the causes of this disease. Dr. Abrams will use these different knockout and mutant models to determine how gene expression in Schwann cells is affected by mutations, and how this change in gene expression leads to axonal death. Schwann cells are very important in that they generate the insulating myelin sheath around peripheral nerves. If successful, the project could provide insights into how genetic defects in supportive Schwann cells cause degeneration of the axons in CMT as well as identify which CMT1X patients may benefit from gene-replacement therapies under development.

https://doi.org/10.55762/pc.gr.84541

Charles Abrams, an associate professor at SUNY Downstate Medical Center in Brooklyn, N.Y., was awarded an MDA research grant totaling $414,787 over a period of three years to study the role of connexin protein mutations in type 1X Charcot-Marie-Tooth disease (X-linked CMT, or CMT1X).

X-linked CMT differs from other types of CMT in that many people with the disease develop central nervous system signs and symptoms in addition to dysfunction of the peripheral nervous system. (In the CNS long nerve tracts convey information through the spinal cord to the brain, and from the brain down the spinal cord to the peripheral, or outer, nerves and muscles. ThePNS is comprised of nerve fibers outside the spinal cord that send signals to the muscles and relay information from the periphery of the body back to the spinal cord and brain.)

More than 300 mutations in the gene for the connexin 32 protein have been linked to CMT1X. Abrams and colleagues will study whether interactions between mutated connexin 32 protein and a related CNS protein, connexin 47, are the cause of the CNS dysfunction found in the disease.

"We are at the early stages in our understanding of the roles of mutations in connexin 32 in the CMT1X disease process," Abrams said. "We have identified some of the ways in which mutations disrupt the function of connexin 32, but we still do not fully understand why these disruptions lead to both peripheral and central nervous system dysfunction."

Funding for this MDA grant began February 1, 2012.

Anthony Antonellis, an assistant professor of human genetics and neurology at the University of Michigan in Ann Arbor, was awarded an MDA research grant totaling $253,800 over three years, to study how mutations in genes that code for specific enzymes cause Charcot-Marie-Tooth disease (CMT). Antonellis and colleagues will conduct experiments in cells to see how genes for enzymes called tRNA synthetases lead to CMT-causing abnormalities and whether restoring the function of these enzymes could be beneficial in treating CMT.

Funding for this MDA  grant began May 1, 2014.

Elisabetta Babetto, a postdoctoral research scholar at Washington University in St Louis, was awarded an MDA research development grant totaling $152,280 over three years to study the possible role of a protein called PHR1 in degeneration of nerve fibers in Charcot-Marie-Tooth disease (CMT).  In experiments in mice with a CMT-like disorder, Babetto will see whether manipulating the biochemical pathway associated with the PHR1 protein can improve the health of nerve fibers. “These experiments will improve our understanding of axonopathy [nerve fiber abnormalities] and have the potential for novel treatments in CMT patients,” she says.

Funding for this MDA grant began May 1, 2014

Robert Baloh, associate professor-in-residence in the department of neurology at the University of California, Los Angeles, has been awarded an MDA research grant totaling $300,000 over three years to study the molecular mechanism of type 2A Charcot-Marie-Tooth disease (CMT) due to mutations in the Mitofusin 2 (MFN2) gene. Baloh has developed a new mouse model that he will use in his research to test whether gene therapy with a gene called MFN1 could serve as a therapeutic approach.

Funding for this MDA research grant began Aug. 1, 2015. 

“Axon degeneration is a central component of irreversible neurological disability in many neuromuscular diseases. There is accumulating evidence that enwrapping glia provide metabolic support to axons, and perturbed metabolic functions in these glia can result in axon degeneration.”

Bogdan Karl Beirowski, assistant professor at the University at Buffalo in Buffalo, New York, was awarded an MDA Research Grant totaling $300,000 over 3 years to study metabolic support of axons by LKB1 signaling in Schwann cells. Dr. Beirowski was the recipient of an MDA development grant in 2012.

Degeneration of long axons is a hallmark in neuropathies and neuromuscular diseases like Charcot-Marie-Tooth (CMT), Friedreich’s ataxia (FA), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA). Axonal losses lead to the debilitating neurological symptoms in these conditions, but underlying mechanisms are only poorly understood. Axons do not exist in isolation but are intimately associated with Schwann cells (SCs), which provide metabolic support to axons. When metabolic functions in these cells are disrupted, it can result in axon degeneration. In CMT neuropathies, it remains unknown how malfunction in SCs results in axon degeneration.

The Beirowski lab recently showed that SCs support integrity of long axons by virtue of their metabolism. Disruption of metabolic function in SCs from transgenic mice results in progressive axon degeneration, recapitulating a key component of human neuromuscular disease. Using genetic mouse models in his laboratory, together with the application of novel technologies to study SC metabolism, Dr. Beirowski and colleagues plan to identify glial metabolic pathways important for regulation of axon integrity and to investigate if abnormalities in such pathways may contribute to nerve damage and axon demise in CMT neuropathy models.

https://doi.org/10.55762/pc.gr.81537

Postdoctoral research scholar Bogdan Beirowski, in the department of genetics at the Washington University School of Medicine in St. Louis, was awarded an MDA development grant totaling $180,000 over three years to study how defective Schwann cells lead to nerve-cell damage in Charcot-Marie-Tooth disease (CMT).

MDA development grants are awarded to exceptional postdoctoral candidates who have the best chance of becoming independent researchers and future leaders of neuromuscular disease research.

Degeneration of axons — fibers that carry electrical signals between the brain and spinal cord and the rest of the body — is a hallmark of CMT and some forms of Dejerine-Sottas disease, and is thought to be responsible for muscle weakness associated with these diseases.

In some forms of CMT, the primary molecular defect localizes to Schwann cells, which normally help nourish and protect axons by wrapping them in a multilayered membrane called myelin. But it's poorly understood how Schwann cell dysfunction causes axon damage.

Data from previous work suggests that removal of defective myelin (demyelination) causes inflammation that results in axon damage, but Beirowski hypothesizes that "defective Schwann cells deprive long axons of metabolic support, thus contributing to axon degeneration."

Beirowski has developed mouse models in which key metabolic regulators are blocked exclusively in Schwann cells, which he now will use to test whether failure of the cells to deliver nutrients to axons could explain axon loss. 

The identification of specific metabolic defects in Schwann cells could lead to the development of CMT therapeutic strategies based on supporting the stability of axons.

Funding for this MDA grant began Aug. 1, 2012.

“Our research is aimed at unravelling how myelination is regulated in the PNS and how perturbation of these mechanisms can cause disease in humans.”

Alessandra Bolino, head of the Human Inherited Neuropathies Unit at IRCCS Ospedale San Raffaele in Milano, Italy, was awarded an MDA Research Grant totaling $300,000 over 3 years to study the targeting of phospholipid and cytoskeleton dynamics to ameliorate CMT neuropathies.

Charcot-Marie-Tooth type 4B1 is a very severe demyelinating neuropathy with childhood onset, characterized by myelin outfoldings, redundant loops of myelin in the nerve that degenerate causing axonal problems. Dr. Bolino’s research previously demonstrated that loss of MTMR2 (Myotubularin-related 2) phosphatase is the cause of the disease. MTMR2 acts on phospholipids, important regulators of membrane trafficking, which is a key process in Schwann cells, the glial cells forming myelin in the peripheral nervous system. Dr. Bolino and colleagues also generated in vitro and in vivo models of CMT4B1, which have been instrumental over the years to study the pathophysiology of this neuropathy.

By investigating the mechanism by which loss of MTMR2 leads to altered membrane trafficking and myelin outfoldings in Schwann cells, they identified a novel signaling pathway that regulates the cytoskeleton dynamics and membrane growth within myelin-forming cells. In this project, they will further characterize this novel pathway and test whether this pathway is a good drug target. These approaches can be extended to other forms of CMT that are characterized by myelin outfoldings (CMT4B2, B3, CMT4C, CMT4H).

https://doi.org/10.55762/pc.gr.81538

Robert Burgess, a professor at The Jackson Laboratory in Bar Harbor, Maine, has been awarded an MDA research grant totaling $300,000 over three years. Burgess and co-investigator Scott Harper, associate professor at Nationwide Children’s Hospital Center for Gene Therapy in Columbus, Ohio, will test an AAV gene therapy approach to specifically block the altered form of the GARS gene in a newly developed mouse model for type 2D Charcot-Marie-Tooth disease (CMT). Successful completion of these studies could lead to a new therapy for type 2D CMT and provide a proof of principle for this approach that may be applicable to other types of CMT.

Funding for this MDA research grant began Aug. 1, 2015.

"Charcot-Marie-Tooth disease (CMT) is a genetic neuromuscular disease, causing muscle weakness, foot deformities, and frequent trips and falls or difficulty walking. There is currently no cure for CMT, but promising treatments are on the horizon."

Joshua Burns, Ph.D., is a Professor of Paediatric Neuromuscular Rehabilitation and Associate Dean Research at the University of Sydney in Sydney, NSW, Australia, has been awarded an MDA Idea Grant totaling $25,000 for one year to develop training and resources and accreditation program for clinical evaluators worldwide to help assess patients with CMT.

A robust clinical outcome assessment (COA) is available online, www.clinicaloutcomemeasures.org, for use with individuals with CMT. The online has over 200 clinical evaluators registered worldwide. To avoid evaluator drift and variability in assessment measurements, online training and accreditation systems are significant especially during the COVID-19 era. Dr. Burns's project aims to make eHealth training and resources available and accredit clinicians to use COAs as a reliable measurement for clinical trials and how to use it accurately.

https://doi.org/10.55762/pc.gr.147562

Gavriel David, an associate professor of physiology and biophysics at the University of Miami’s Miller School of Medicine in Florida, has been awarded an MDA research grant totaling $253,800 over three years to study calcium overload in nerve cells in Charcot-Marie-Tooth disease (CMT). David and colleagues have previously studied mice with CMT-causing genetic defects that disrupt the myelin sheath that coats nerve fibers, finding that disrupted myelin sheaths are associated with abnormally large increases in calcium in nerve cells. Now, they will investigate the apparent relationship between disrupted myelin and calcium overload, with an eye to treating CMT.

Funding for this MDA grant began May 1, 2014.

Alan A. and Edith L. Wolff Professor of Developmental Biology Aaron DiAntonio at Washington University school of Medicine in St. Louis was awarded an MDA research grant totaling $300,000 over three years to identify novel targets to block nerve degeneration in Charcot-Marie-Tooth disease (CMT). DiAntonio will perform a genetic screen in fruit flies to identify genetic suppressors of nerve degeneration and then test these targets in human nerve cells in a dish. The resulting targets will be potential candidates for the treatment of peripheral neuropathy and other disorders in which motor axons are lost.

Funding for this MDA research grant began Aug. 1, 2015.

“There is currently no disease-modifying treatment for CMT2A; mitofusin agonists may be the first. This is an orphan disease with a clear unmet need.”

Gerald W. Dorn, II, MD, professor of Medicine and director of the Center for Pharmacogenomics at Washington University School of Medicine in St. Louis and president of Mitochondria in Motion, Inc., was awarded an MDA research grant totaling $267,942 over two years to study mitofusin agonists to treat Charcot-Marie-Tooth disease (CMT).

There are many subtypes of CMT, each caused by different genetic mutations. CMT type 2A (CMT2A) is caused by mutations in the mitofusin 2 gene (MFN2), which regulates mitochondrial fusion and motility. Affected mitochondria are fragmented, dysfunctional, and immobile, leading to the symptoms of CMT, which include muscle weakness, atrophy, and loss of sensation in the lower legs and feet and sometimes the hands, wrists, and forearms.

Dr. Dorn previously discovered a compound that can act like the missing mitofusin in CMT2A. This mitofusin agonist has been shown to improve CMT2A mitochondrial abnormalities in human and mouse tissue culture models. Dr. Dorn recently helped found a biotechnology company, Mitochondria in Motion, and he will use the new MDA funding to modify the company’s lead compound to make it more “drug-like” and then show that this improved drug can halt or reverse the progression of CMT2A in a humanized mouse model. It is hoped that this will move the field closer to first-in-human clinical trials for this new class of drugs.

https://doi.org/10.55762/pc.gr.87353

Vera Fridman, at Massachusetts General Hospital in Boston, was awarded an MDA clinical research training grant totaling $180,000 over a period of two years to the effects of Serine in people with a form of Charcot-Marie-Tooth (CMT) disease called hereditary sensory and autonomic neuropathy type 1 (HSAN1).

CMT is the most commonly inherited neurological disorder, affecting 1 in 2,500 people worldwide. It is a slowly progressive disorder, causing degeneration of the peripheral nerves that control sensory information coming from the limbs. HSAN is a rare genetic neuropathy that causes severe numbness, weakness and ulceration of the feet and hands.

Two abnormal lipids (fat-like substances) have been identified in the blood of both humans and mice with HSAN1. It has been shown that levels of these lipids can be reduced by administering the amino acid serine, and that mice treated with serine have better motor and sensory function.

Fridman’s goal is to determine the effect of serine on symptoms of people with HSAN1 in order to assess whether serine supplementation may be an effective therapy for the disease.

Funding for this MDA grant is effective July 1, 2013.

"The overall goal of this project is to develop new and innovative mobile device-compatible methodologies based on low-cost easily obtained accelerometers and machine learning algorithm technologies with the objective of providing cost-efficient tools to allow consumers, clinicians and researchers to better evaluate the community mobility of people with neuromuscular diseases in clinical and research settings."

Erik Henricson, Assistant Professor of Physical Medicine and Rehabilitation at the University of California, Davis, was awarded an MDA Clinical Research Grant totaling $427, 822 to develop an automated sensor technology to evaluate ambulatory function in people with neuromuscular disease in the home, community, and clinical settings.

A number of potential therapies are in clinical development for neuromuscular diseases, with a growing recognition that treatment benefit will be greater the earlier it is initiated. Although many children are being diagnosed as toddlers or younger, they are rarely included in clinical trials because of the lack of reliable clinical endpoints for longitudinal follow-up.

Dr. Henricson has developed a machine learning algorithm that calibrates data from a single small sensor to determine gait characteristics, even in children, with a high degree of accuracy. In this project he will work with male and female patients with DMD, BMD, SMA, FSHD and CMT to further the development of this reliable, unobtrusive, easy-to-use, portable, and cost-effective technology that pairs with the patient’s own mobile device.

https://doi.org/10.55762/pc.gr.140910

Peter Hiesinger, associate professor at the University of Texas Southwestern Medical Center in Dallas, was awarded an MDA research grant totaling $300,000 over a period of three years to investigate the causes of type 2B Charcot-Marie-Tooth disease (CMT2B).

CMT2B is caused by mutations in a gene called rab7. The protein made from the gene performs a critical function in the degradation of debris in all cells. “Even though the gene is known, it is unclear how the mutations found in patients affect the gene’s function,” Hiesinger says. Without knowing how the mutation causes disease, it is difficult to design a therapy to treat it. He has developed models of the disease that suggest the mutation causes the protein to no longer be active, and that this loss of function affects nerve cells before other cells in the body.

“Our findings explain the genetic dominance [only one mutant copy of the gene, from either parent, is needed to develop the disease] and reveal a particular sensitivity of nerve cells for a defect in debris removal,” says Hiesinger. “This discovery opens the door for an understanding and a potential therapy of CMT2B based on the molecular manipulation of the underlying cause.

“Importantly,” he adds, “we suggest an increase of rab7 function as a therapeutic opportunity, in contrast to the currently suggested reduction of mutant gene function.”

In this project, Hiesinger will test this hypothesis of disease in a fly model of CMT2B and investigate rab7 function in detail.

Funding for this MDA grant began August 1, 2013.

Henry Houlden, professor of neurology at the MRC Centre for Neuromuscular Diseases, University College London Institute of Neurology in England, was awarded an MDA research grant totaling $288,151 over three years to elucidate the genetic causes of severe forms of Charcot-Marie-Tooth disease (CMT) and other types of early-onset neuropathy. Identification of the causative genes could help optimize treatment strategies and accelerate new therapy development.

Funding for this MDA research grant began Feb. 1, 2016.

Nivedita Jerath, a clinical fellow in neuromuscular medicine at the University of Iowa, has been awarded an MDA clinical research training grant to study driving ability in patients with the type 1A form of Charcot-Marie-Tooth disease (CMT). Because of difficulties with strength and balance, as well as foot abnormalities and tight ankles, the disease may affect driving, which requires quick responses, such as slamming on the brakes or turning the steering wheel quickly. Using a driving simulator as well as a special car that can videotape driver performance on the road, Jerath will investigate whether or not patients with CMT1A can drive normally. If they are found to have driving difficulties, Jerath says, she hopes the findings can be used to develop devices that might help people with CMT1A to drive more safely.

Funding for this MDA grant began July 1, 2014

MDA awarded a grant totaling $282,630 to Albena Jordanova, professor in the department of genetics at the University of Antwerp, Belgium, for research into the molecular causes of, and potential drug targets for, a recently discovered form of Charcot-Marie-Tooth (CMT) disease known as dominant intermediate CMT type C (DI-CMTC).

Jordanova's research team was the first to describe the new CMT type and showed that the disease is caused by different mutations (genetic flaws) in the gene that carries instructions for an enzyme called tyrosyl-tRNA synthetase (YARS).

In their new work, Jordanova and colleagues aim to identify genes that modify the neurodegenerative symptoms of DI-CMTC present in a fruit fly research model of the disease. The team will then test the modifying genes to determine how well each is able to interact with drug-like chemical compounds, in an effort to pinpoint the best drug targets for DI-CMT and other types of the disease.

The "best gene hits" will be those that carry instructions for proteins that are both structurally favorable — that is, their protein folds are amenable to interactions with drug-like chemical components — and functionally favorable with a proven ability to affect the DI-CMTC disease process.

"MDA funding is absolutely essential to start this work," Jordanova said. "This is important seeding money for us to initiate a midterm research program and to perform the research we dream of."

Funding for this MDA grant began August 1, 2010.

"By establishing an effective, clinically applicable gene therapy approach targeting peripheral nerves, we may be able to develop treatments for a number of other similar inherited neuropathies or even for more common acquired neuromuscular disorders such as motor neuron disease and inflammatory neuropathies."

Kleopas Kleopa, MD, professor and senior consulting neurologist at the Cyprus Institute of Neurology and Genetics, Cyprus School of Molecular Medicine, in Nicosia, Cyprus, was awarded a research grant jointly funded by the Charcot-Marie-Tooth Association (CMTA) and MDA totaling $276,430 over three years to perform critical, proof-of-concept studies to test whether delivery of the connexin 32 gene (Cx32) using an adeno-associated virus (AAV) vector can improve symptoms in a mouse model of CMT1X, as well as determine the optimal route for delivery of the therapy.

Mutations in the gene coding for the gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), are associated with the X-linked form of Charcot-Marie-Tooth disease (CMT1X), which affects approximately 1 in 25,000 people and is the second-most-common form of CMT. With previous MDA-funded support, Dr. Kleopa pioneered a gene therapy approach to treat CMT1X, showing that a single spinal injection of the Cx32 gene was associated with production of normal protein in nerves and improvement of peripheral nerve health and motor performance in a mouse model of CMT. In a follow-up study co-funded by the MDA and the CMTA, he examined whether repeated injections in mice led to increased protein levels and tested whether treatment at later stages of the disease led to improvement like that seen for treatment in the early stages.

The target cell type for this therapy is the Schwann cell, which generates the insulating myelin sheath around peripheral nerves. The challenge for CMT1X and other demyelinating forms of CMT is optimizing delivery of the gene to Schwann cells. In previous studies, Dr. Kleopa employed a different type of viral vector to deliver the Cx32 gene, but for this new study he will adapt this approach to AAV, which has been more widely used in the nervous system and shown promise in clinical studies for other diseases. The project will test several types of AAV and different injection paradigms to determine the best method to restore the function of Cx32 in Schwann cells. Positive results may help advance development of treatments for other types of CMT affecting Schwann cells, as a similar AAV approach can be applied to CMT1A and other subtypes of CMT1.

https://doi.org/10.55762/pc.gr.84552

Kleopas Kleopa, professor at the Cyprus Institute of Neurology and Genetics in Nicosia, Cyprus, was awarded an MDA research grant totaling $280,945 over a period of three years to develop gene therapy in a mouse model of X-linked Charcot-Marie-Tooth disease (CMT).

CMTX is due to mutations in the gene for connexin 32. This protein forms connections between layers of the insulating material around nerve cells, called myelin. Loss of connexin prevents the nerve cell from functioning properly, leading to muscle atrophy, weakness and sensory loss in the limbs. Kleopa has generated a mouse model of the disease, and has developed virus-like particles that can carry a functional copy of the gene, increasing connexin 32 protein production when delivered directly to the nerve.

Now, Kleopa will study a combination of gene delivery methods, including direct injection into the nerves, muscles and spinal cord. He also will examine treated mice for signs that the gene improves neuropathy (nerve abnormalities).

“Transgenic mice are particularly well suited for this study because treatment of peripheral neuropathy can only be validated in a vertebrate animal model, where the pathology can be studied in peripheral nerves,” Kleopa says. “Furthermore, this particular mouse model reproduces all major pathological aspects of the human disease, and therefore it is relevant to test potential treatments.

“In the last two decades research in the field of inherited neuropathies, especially the common forms, has provided many insights into the causes and mechanisms of disease. Developing genetic treatments, using the recently generated disease models, is an important and timely approach to also provide potential therapies for these disorders in the near future.”

Funding for this MDA grant began August 1, 2013.

Kleopas Kleopa, professor and senior consulting neurologist at the Cyprus Institute of Neurology and Genetics, Cyprus School of Molecular Medicine, in Nicosia, Cyprus, was awarded an MDA research grant totaling $119,999 over a period of two years to test whether gene therapy treatment after disease onset could lead to functional improvements in CMT1X, the second most common form of Charcot-Marie-Tooth disease (CMT).

With previous MDA support, Kleopa and colleagues pioneered a gene therapy approach to treat the X-linked form of CMT, showing that a single lumbar injection of the gene that is mutated in the disease was associated with production of normal protein in nerves and improvement of peripheral nerve health and motor performance.

Kleopa’s new work, co-funded by the CMT Association, will advance and expand on this approach as his team examines whether repeated injections can lead to increased protein levels, and tests whether treatment at later stages of the disease can lead to improvement similar to that seen for treatment in the early stages.  

Funding for this MDA research grant began Feb. 1, 2017.

Ronald Liem, professor of pathology and cell biology at Columbia University Medical Center in New York, N.Y., was awarded an MDA research grant totaling $318,264 over a period of three years to study the progression of disease in a mouse model of type 2E Charcot-Marie-Tooth (CMT) disease.

CMT is the most commonly inherited neurological disorder, affecting 1 in 2,500 people worldwide. It is a slowly progressive disorder, causing degeneration of the peripheral nerves that control sensory information coming from the limbs. CMT2E is caused by mutations in the gene for a protein called neuronal intermediate filament light (NFL). NFL provides stability to axons, the long extensions of muscle-controlling motor nerve cells called motor neurons that allow them to control muscle contractions.

Liem’s lab has created a mouse model of CMT2E by introducing a mutated copy of the gene. Their preliminary results indicate the mouse develops many of the same features as people with the disease, including deficits of movement and hearing. “We believe that this new mouse model is likely the best model of CMT type 2E and will allow us to study the progression of the disease at a level that is not possible in human subjects. We expect that the mouse model will also be useful for testing therapeutic compounds when they become available,” Liem says. 

Liem will be performing detailed developmental and anatomic studies to follow the progression of the disease in mice, and to learn more about exactly how the mutation causes problems. One focus will be on the effects of the mutation on mitochondria, the cell’s "powerhouses," which are believed to be involved in CMT.

“These studies will give us a better understanding of the mechanisms by which nerve damage occurs as a result of this mutation,” Liem says. “We expect that the mouse model also will be useful for testing therapeutic compounds when they become available.”

Funding for this MDA grant began Feb. 1, 2013.

Charcot-Marie-Tooth disease (CMT) includes a group of inherited peripheral neuropathies that cause symptoms of progressive weakness and loss of sensation. CMT is the most common inherited neurological condition worldwide, but there are currently no available treatments to slow progression of any forms of this disease. A subtype of CMT, known as CMT type 2C, is caused by mutations in TRPV4, which is an ion channel that can open or close to allow calcium to enter cells. Our work in animal models of this condition has shown that disease mutations in TRPV4 cause the channel to be overactive, and drugs that block the channel are highly effective as treatments in these animal models. This suggests that available TRPV4 blocking drugs are a promising potential treatment for patients with TRPV4 mutations. However, there are still important barriers that need to be overcome in order to facilitate a clinical trial for this condition. In particular, the natural progression of CMT2C and readouts of disease progression must be better defined to determine the specific outcome measures that would be used in a clinical trial. This proposal will use a comprehensive clinical approach to define markers of disease severity and progression in patients, an essential step in the process of moving towards a clinical trial and ultimately establishing a treatment for CMT2C. If successful, this would be a ground-breaking accomplishment and pave the way for clinical trials for other forms CMT.

https://doi.org/10.55762/pc.gr.157002

MDA awarded a research grant totaling $357,366 over three years to Jeffrey Milbrandt, professor and head of the department of genetics, and professor of pathology & immunology, medicine and neurology at Washington University School of Medicine in St. Louis.

The funds will help support Milbrandt's work in determining how Schwann cells contribute to nerve damage (neuropathy) in neuromuscular diseases such as Charcot-Marie-Tooth disease (CMT) and Friedreich's ataxia (FA).

Neuropathies and neuromuscular diseases like CMT and FA are associated with poor function of mitochondria, the energy producer in cells.

In previous work, Milbrandt and colleagues found that mice with mitochondrial deficits in Schwann cells develop a progressive neuropathy. (Schwann cells are a type of support — or glial — cell in the nervous system outside the brain and spinal cord; they support the function and maintenance of nerve fibers, or axons.)

Milbrandt's new project focuses on determining how Schwann cells obtain their energy when their mitochondria are damaged, and the mechanisms by which Schwann cell metabolism causes damage to the peripheral nerves (bundles of nerve fibers that run between the spinal cord and the muscles). He also plans to test whether pharmacological interventions to manipulate Schwann cell metabolism will help restore normal peripheral nerve function.

"For these studies, we will use a mouse model in which mitochondria are dysfunctional specifically and exclusively in Schwann cells," Milbrandt explains. "These mice, called Tfam-SCKO mice, are a good model for these studies because they develop many critical features of human neuromuscular disease and peripheral neuropathy."

Millbrandt notes: "Peripheral neuropathy research is entering a new era as we learn more about how axons are dismantled and the role of glia in maintaining axon health. There are unparalleled opportunities now to develop new treatments for this debilitating condition that is reaching epidemic proportions worldwide."

Funding for this MDA grant began Aug. 1, 2012.

Kelly Monk, an assistant professor of developmental biology at Washington University in St. Louis, was awarded an MDA research grant totaling $253,800 over three years to investigate a possible therapeutic avenue for treating Charcot-Marie-Tooth disease (CMT)  and the related Dejerine-Sottas disease (DSD). Monk and her colleagues have previously found that a protein called GPR126 is required for proper formation and maintenance of the myelin sheath that insulates fibers in the peripheral nervous system, and they will now study how this protein controls this process, which is known as myelination. They will also look at the role of a related protein called GPR56 and will investigate whether either or both of these proteins could represent new drug development targets for CMT or DSD.

Funding for this MDA grant began May 1, 2014.     

MDA has awarded a research grant totaling $420,000 over three years to Thien Nguyen, assistant professor in the department of neurology at Johns Hopkins University School of Medicine in Baltimore. The new funds will help support Nguyen’s research into the breakdown of peripheral nerves (nervous tissue that connects the spinal cord with muscles and sensory organs) in Charcot-Marie-Tooth disease (CMT).

Degeneration of the axons (the long fibers that carry signals from nerve cell bodies to muscle) is a hallmark of type 1 CMT and is the primary determinant of the severity of symptoms in people with the disease. It follows that prevention of axonal degeneration should improve clinical outcomes for people with CMT1.

The same principle also should be applied to other types of CMT, Nguyen noted.

In previous studies, Nguyen and colleagues have determined that mutations in genes for myelin-making cells called "Schwann cells" can lead to mutant Schwann cells that may instruct axons to degenerate through certain specific signaling molecules that normally promote stability and survival, including one called myelin-associated glycoprotein (MAG). Study results out of Nguyen's lab have suggested that another signaling molecule, called netrin-1, may play an important role in axonal survival in CMT, making it a potential therapeutic target.

The investigators will determine whether increasing netrin-1 activity might prevent axonal degeneration in cell culture and in a research mouse model.

Findings from Nguyen’s work could reveal the potential therapeutic benefit of netrin-1 and lead to its development as a neuroprotective therapeutic for CMT.

"In theory, results from the project also could be expanded to axonal degeneration even without demyelination," Nguyen said. "Thus, there could be applicability to many of the neurodegenerative disorders covered by MDA."

Funding for this MDA grant began February 1, 2011.

MDA awarded a research grant totaling $420,000 over three years to professor Garth Nicholson at the ANZAC Research Institute, University of Sydney in New South Wales, Australia.

The funds will help support Nicholson's research into the biological and cellular effects caused by mutations in the copper transport gene ATP7A in Charcot-Marie-Tooth disease (CMT).

Nicholson and colleagues have discovered that mutations in the copper transport gene ATP7A cause slow but progressive degeneration of the long ends (axons) of the nerve cells called motor neurons that send signals to the limb muscles.

The ATP7A protein is essential for human copper metabolism; it is involved with the delivery of copper for physiological processes, and also in maintaining copper balance in humans.

Nicholson's team has shown that mutant ATP7A protein does not traffic copper properly in the presence of elevated copper levels. Now it plans to determine whether ATP7A mutations cause disease symptoms by a mild reduction in intracellular copper movement from motor neurons, or whether the mutations work by some other mechanism such as poor delivery of copper to the distal axon, due to the trafficking defect.

Using human cellular and research mouse models, the investigators plan to determine the biological and cellular effects of the impaired ATP7A trafficking. They will investigate the role of interacting proteins in ATP7A trafficking relevant to axonal copper delivery as a means of exploring the possible mechanistic links between motor neuron disorders and copper; and they will establish a transgenic mouse model that carries mutations in the ATP7A gene.

Funding for this MDA grant began February 1, 2012.

“Our research aims to develop unbiased experimental strategies and tools to systematically address critical roadblocks in the identification and functional annotation of causative disease alleles in neuromuscular diseases.”

Wolfgang Pernice, PhD, a postdoctoral fellow in Neurology at Columbia University Medical Center in New York, was awarded an MDA development grant totaling $210,000 over three years to more accurately associate rare genetic variants to multiple neuromuscular diseases (NMDs).

For many major NMD categories, the causative gene can be identified in less than 50% of the cases. One of the complicating factors is that in many cases, rare gene variants are identified, but it’s unknown if a variant causes the disease or is harmless. Lacking are efficient, unbiased experimental strategies to systematically evaluate the relevance of these individual variants in disease. Likewise, it’s not known how many of these genes function in healthy individuals.

As a new MDA grantee, Dr. Pernice will use a novel imaging-based method and advanced machine learning to screen for disease-associated phenotypes in patient-derived cells with genetically confirmed NMDs, including Charcot-Marie-Tooth disease and mitochondrial myopathies. This method will allow him to establish a reference dataset by which to directly compare and evaluate new candidate mutations and conduct pharmacological screens for potentially therapeutic agents.

https://doi.org/10.55762/pc.gr.87332

“We are grateful to MDA for its support of this extremely important work,” Mary Reilly said. “The results from our pilot study of an MRI neuromuscular protocol in CMT1A are promising and we anticipate we will be able to confirm responsiveness with a refined protocol in children with CMT1A and in the other three common types of CMT.”

Mary M. Reilly, professor of clinical neurology and consultant neurologist, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, was awarded an MDA human clinical trials grant totaling $1 million to evaluate a new magnetic resonance imaging (MRI) protocol designed to detect disease-related changes in muscles over time in Charcot Marie Tooth disease (CMT).

In CMT, damaged motor nerves are unable to send adequate signals to muscles. This leads to muscle weakness and wasting, as well as other abnormal changes including the accumulation of fat in muscle tissue, which can be detected by MRI.

Reilly’s team has developed an MRI protocol to measure fat accumulation in thigh and calf muscles. In a pilot study to determine the protocol’s effectiveness at measuring fat infiltration in adults with CMT1A, Reilly’s team showed that the presence of calf muscle fat increased significantly over a 12-month time period.

With the new MDA funding, the team will work to refine the new protocol to include foot muscles, which could make it effective in mild cases of CMT where fat accumulation occurs more often in the feet than in calves. The team will study the refined protocol in children with CMT1A, as well as in the other three most common types of CMT: CMT1B, CMT2A and CMTX.

If successful, Reilly’s work could result in a sensitive, validated outcome measure in multiple forms of CMT, in both children and adults, that could allow researchers conducting clinical trials to reliably detect any positive effects of a candidate treatment within a 1- to 2-year timeframe.

https://doi.org/10.55762/pc.gr.79107

"Rational clinical trials in CMT with outcome measures that can measure effectiveness are in place and will hopefully lead to effective treatments within the next three to five years for many subtypes."

Michael Shy, PhD, professor of Neurology and Pediatrics at the University of Iowa, was awarded an MDA Clinical Research Network Grant (CRNG) totaling $423,413 over three years to further develop the Inherited Neuropathies Consortium (INC), a network of clinical investigators dedicated to evaluating therapies for patients with inherited peripheral neuropathies, collectively known as Charcot-Marie-Tooth disease (CMT).

In CMT peripheral nerves degenerate, typically resulting in muscle weakness and sensory loss in the hands, arms, feet, and legs. The disease is progressive; however, the severity of symptoms and rate of progression depend on the type of CMT.

Dr. Shy has a long history of MDA funding, including receiving awards to create the North American CMT Network and to establish the North American CMT Consortium. His last grant was awarded for the Inherited Neuropathies Consortium (INC), an international collection of centers devoted to developing treatments for and treating patients with CMT.

With this most recent funding, Dr. Shy will expand the INC’s natural history data to become “clinical-trial-ready” for common and rare forms of CMT; identify, characterize, and facilitate treatments for novel forms of CMT; train future investigators in the field; and share INC data with scientists, physicians, and patients in an easily accessible manner.

The Inherited Neuropathy Consortium is dedicated to developing the infrastructure necessary to evaluate therapies for patients with Charcot-Marie-Tooth disease. We have developed CMT specific clinical outcome assessments to measure the effects of CMT on adults and children. We have identified markers of disease severity in blood, from skin biopsies and also by MRI imaging of muscles. We have had a Critical Path Innovation Meeting with the FDA on how best to use our measures to bring successful clinical trials to our patient population. Developing rational therapies for patients requires knowing the cause of their CMT. We have identified 23 novel genetic causes of CMT. We have initiated the CMT Variant Browser which promotes sharing of genetic information on CMT for patients, their families, caregivers and researchers. We have successfully trained 14 young investigators to carry on future CMT research, many of whom have obtained faculty positions in fields related to CMT. We are applying to continue MDA support through 2024 which coincides with the end of our currently funded NIH five year cycle to continue natural history studies with various CMT subtypes, continue gene identification and genetic modifier studies using whole genome sequencing, develop the use of remote evaluations of patients and train future investigators.

https://doi.org/10.55762/pc.gr.157060

Michael Shy, a professor of neurology and pediatrics at the University of Iowa, has been awarded an MDA research grant totaling $253,800 over three years to develop a clinical trial to test a treatment for patients with the type 1B form of Charcot-Marie-Tooth disease (CMT). Based on previous MDA-supported work in mice with a CMT1B-like disorder, Shy and colleagues believe that treating a cellular phenomenon called the ER stress response may help CMT1B patients.

Funding for this MDA grant began May 1, 2014. 

Michael Shy, a professor of neurology and pediatrics at the University of Iowa, has been awarded an MDA research grant totaling $253,800 over three years to develop a clinical trial to test a treatment for patients with the type 1B form of Charcot-Marie-Tooth disease (CMT). Based on previous MDA-supported work in mice with a CMT1B-like disorder, Shy and colleagues believe that treating a cellular phenomenon called the ER stress response may help CMT1B patients.

Funding for this MDA grant began May 1, 2014. 

Unravelling the molecular mechanism underlying an incurable disease Charcot-Marie-Tooth (CMT) is an incurable disease in which motor and sensory nerves degenerate, leading to muscle weakness and sensory deficits. CMT is a genetic disease, and changes in many different genes can cause CMT. It is incompletely understood how these changes in CMT genes ultimately result in degeneration of motor and sensory nerves. Currently, no effective drug treatment is available for any genetic form of CMT. Among the CMT genes, mutations in 6 distinct genes that produce so-called ‘transfer RNA (tRNA) synthetases’ cause CMT. Scientists recently elucidated a novel mechanism that underlies CMT caused by mutations in one of these tRNA synthetases, the glycyl-tRNA synthetase. Now, they wish to evaluate whether a similar mechanism applies to CMT caused by mutations in the other tRNA synthetase genes. If so, this would imply that administration of tRNA may constitute a novel therapeutic approach for these incurable diseases.

Image Source: Prinses Beatrix Spierfonds

https://doi.org/10.55762/pc.gr.157000

Erik Storkebaum, independent Max Planck Research group leader at the Max Planck Institute for Molecular Biomedicine in Münster, Germany, was awarded an MDA research grant totaling $291,000 over three years to study the underlying mechanisms that drive the disease process in Charcot-Marie-Tooth disease (CMT).

Familial forms of neurodegenerative diseases are caused by mutations in single genes. In an individual person, a single mutation in a neurodegeneration gene causes disease, but across a range of people, different mutations in the same disease gene typically occur. Furthermore, for a given neurodegenerative disease, distinct disease genes often encode proteins that function in the same molecular or cellular pathway.

It is unknown whether mutations in related genes, or even in a single gene, cause disease through a common molecular mechanism, or whether different mutations cause disease through disparate mechanisms. This is a key question from a therapeutic perspective, as common mechanisms may allow for unified therapeutic approaches.

Mutations in five distinct genes encoding proteins called tRNA synthetases, which play an essential role in the production of proteins in cells, all cause CMT. Storkebaum and colleagues will work with fruit fly models of CMT to determine whether different mutations across four distinct tRNA synthetase genes cause disease through the same or through disparate molecular mechanisms.

Should the results indicate that all mutations cause disease through a similar molecular mechanism, it could guide development of a common therapeutic approach to treat all forms of CMT caused by mutations in tRNA synthetases.

Funding for this MDA research grant began Feb. 1, 2017.

Daniel Summers, a postdoctoral research scholar in the department of genetics at Washington University School of Medicine in St. Louis, was awarded an MDA development grant totaling $180,000 over three years to investigate how activation of a protein called SARM leads to the loss of metabolites that are essential for the health of peripheral nerves in Charcot-Marie-Tooth disease (CMT). Further knowledge of this pathway may highlight whether blocking SARM may be a novel therapeutic approach for CMT and other peripheral neuropathies.

Funding for this MDA development grant began Aug. 1, 2015.

Charlotte Sumner, MD, professor of Neurology and Neuroscience at Johns Hopkins University School of Medicine in Baltimore, was awarded an MDA research grant totaling $300,000 over three years to study the role of mutations in the transient receptor potential vanilloid 4 gene (TRPV4) in causing one type of Charcot-Marie-Tooth disease (CMT) and distal spinal muscular atrophy (SMA).

CMT is characterized by the degeneration of peripheral nerves, resulting in disabling muscle weakness and sensory loss. One form of the disease, CMT type 2C (CMT2C), is caused by mutations in TRPV4, which codes for a cellular membrane channel protein that helps control the flow of calcium in and out of cells. Mutations in TRPV4 cause CMT2C and distal SMA, revealing an unexpected role for this Ca2+-permeable channel in neurodegeneration.

In previous MDA-funded research, Dr. Sumner generated fly and mouse models of CMT2C in order to better understand the mechanisms of disease. With this newest MDA grant, Dr. Sumner will focus on the role that TRPV4 may play in endothelial cells regulating the blood-nerve barrier. Defining the mechanisms by which TRPV4 mutations cause neuropathy is important because TRPV4 protein is a readily druggable therapeutic target — it is expressed at the plasma membrane and small molecules acting on it already exist.

Charlotte Sumner, associate professor of neurology and neuroscience at Johns Hopkins University School of Medicine in Baltimore, Md., was awarded an MDA research grant totaling $300,000 over a period of three years to study the effects of the gene that causes one form of Charcot-Marie-Tooth disease (CMT).

CMT is characterized by the degeneration of peripheral nerves, resulting in disabling muscle weakness and sensory loss. One form of the disease, called type 2C CMT (CMT2C), is caused by mutations in a gene calledTRPV4 that helps control the flow of calcium in and out of cells. “Our long-term goal is to determine how mutations in TRPV4 lead to CMT2C and to develop treatments for this disease,” Sumner says.

Some effects of these gene mutations are known, but how they cause nerve degeneration is still unclear. Sumner has generated fly and mouse models of CMT2C in order to pursue that question. “The advantage of using fruit flies is that they allow us to rapidly evaluate the effects of multiple mutations and potential disease modifiers, as well as to assess TRPV4 function by calcium imaging.” The mouse, in turn, better mimics aspects of human physiology affected in the disease and can be used to test drugs.

“Together, these studies will provide important insights into the cellular and molecular mechanisms underlying TRPV4-mediated nerve disease, and in the future, we plan to use these fly and mouse models synergistically to develop new therapeutic interventions,” she says. “Because it is an ion channel expressed at the cell surface membrane [and therefore potentially accessible by therapeutic compounds], TRPV4 inhibition represents an attractive therapeutic strategy for patients with CMT2C.”

Funding for this MDA grant began August 1, 2013.

“If we can successfully validate our research hypothesis, reducing the expression of HSPB8 in vivo and decreasing the detrimental effects of the mutant protein, we may have found the first-ever treatment for dHMN patients having HSPB8 mutations. To reach this objective, we will focus on already-approved compounds and anti-sense oligonucleotides (ASOs).”

Vincent Timmerman, group leader at the University of Antwerp in Belgium, was awarded an MDA Research Grant totaling $300,000 over 3 years to study neuromuscular disease caused by HSPB8 mutations.

Patients with distal hereditary motor neuropathy, a variant of Charcot-Marie-Tooth neuropathy, have a progressive degeneration of their peripheral nerves resulting in muscle weakness and atrophy. Dr. Timmerman and colleagues were the first to report disease-causing mutations in the HSPB8 gene. The small heat shock protein B8 (HSPB8) belongs to the “stress protein family” and is expressed in various tissues and cells. HSPB8 acts as a molecular chaperone by clearing protein aggregates and reducing their toxic accumulation. This protective function has been studied in the context of cancer and neurodegenerative disease.

Building on the discovery, Dr. Timmerman’s team generated a mouse model mimicking the disease by introducing a mutation in the Hspb8 gene (a “knock-in” mouse). In addition, the team also made a model in which they deleted Hspb8 (a “knock-out” mouse), and these animals developed a mild myopathy.

The next step aims to identify therapeutic compounds that can rescue or delay the neurodegeneration observed in the knock-in model, or that can result in a milder phenotype as seen in the knock-out animals. The identified small-molecule compound acting on the expression of HSPB8 could be beneficial to treat patients affected with distal hereditary motor neuropathy and also patients with distal myopathies and related neuromuscular disorders.

Ludo Van Den Bosch is investigating the possible use of a compound known as an HDAC6 inhibitor in treating type 2F CMT and possibly other disorders of the nervous system.

Charcot-Marie-Tooth Disease (CMT)

Ludo Van Den Bosch, a professor in the Department of Neurosciences at KU Leuven in Leuven, Belgium, was awarded an MDA research grant totaling $235,020 over three years to study the type 2F form of Charcot-Marie-Tooth disease (CMT) and investigate a possible treatment for it.  Van Den Bosch and colleagues will conduct experiments in mice with a disorder mimicking human CMT2F, which have been shown to benefit from treatment with a compound known as a histone deacetylase 6 (HDAC6) inhibitor. They hope to find that HDAC6 inhibition has the potential to treat CMT2F and possibly other disorders of the nervous system, including perhaps other forms of CMT.

Funding for this MDA grant began May 1, 2014.

"An open Charcot-Marie-Tooth genetics data resource could help expedite CMT research, from gene identification to drug discovery and development."

Stephan Zuchner, M.D., Ph.D., chairman of the Dr. John T. Macdonald Foundation Department of Human Genetics at the University of Miami School of Medicine in Florida, was awarded an MDA research infrastructure grant totaling $384,967 over three years to expand and make more widely available resources to streamline gene identification and therapy development efforts for Charcot-Marie-Tooth disease (CMT).

Approximately 40 percent of people with CMT do not have a confirmed genetic diagnosis, highlighting the need for a continued focus on gene identification efforts for CMT. Since the most common causative genes for CMT have already been identified, there exists a need for genetic analysis across larger cohorts of patients to find rare causes of disease. In collaboration with the Inherited Neuropathy Consortium, Dr. Zuchner has developed a genomic data infrastructure platform. This open CMT genetics data resource allows for aggregation, archiving, analysis, comparison and sharing of genetic data among many laboratories and institutions.

The resource will accelerate CMT research from gene identification to therapy discovery and development. Making such data available to CMT researchers in the United States and around the world could improve diagnostic processes, guide functional studies and drug discovery, and build the foundation for the patient selection process necessary for well-designed clinical trials.

https://doi.org/10.55762/pc.gr.140810

Stephen Züchner, associate professor of human genetics and neurology at the University of Miami Miller School of Medicine in Florida, was awarded an MDA research grant totaling $390,000 over three years to identify genes responsible for Charcot-Marie-Tooth disease (CMT).

"Genetic research over the past 25 years has identified more than 50 different CMT genes,” Züchner explains. “While the subtype CMT1 is largely explained by these genes, CMT2 and a number of other subtypes of CMT are less well-understood.”

It’s thought that many more genes need to be found to explain the majority of CMT found in people with the disease, but a new generation of DNA sequencing machines — called next-generation sequencers — is making that endeavor much easier and cheaper

“We have been pioneering the application of these new instruments for neuromuscular and other diseases,” Züchner says, “and have already identified and published multiple novel genes using this approach in a number of diseases.”

In his new work, Züchner and colleagues are focused on identifying additional genes that cause CMT.

“We believe that the more genes we know, the better will be our understanding of gene networks that work together in a process that leads to disease,” Züchner says. “Instead of focusing on a single gene, there will be benefits in understanding the entire disease process.”

Such understanding may lead to development of therapies that, instead of targeting a specific gene, influence gene networks or pathways — meaning a single treatment could help people with mutations in different genes.

Funding for this MDA grant began Aug. 1, 2012.

An open Charcot-Marie-Tooth genetics data resource could help expedite CMT research, from gene identification to drug discovery and development.

Stephan Zuchner, chairman of the Dr. John T. Macdonald Foundation of Human Genetics at the University of Miami School of Medicine in Florida, was awarded an MDA research infrastructure grant totaling $384,967 over three years to expand and make more widely available resources to streamline gene identification and therapy development efforts for Charcot-Marie-Tooth disease (CMT).

Approximately 40 percent of people with CMT do not have a confirmed genetic diagnosis, highlighting the need for a continued focus on gene identification efforts for CMT. Since the most common causative genes for CMT have already been identified, there exists a need for genetic analysis across larger cohorts of patients to find rare causes of disease.

In collaboration with the Inherited Neuropathy Consortium, Zuchner is working to develop a genomic data infrastructure platform. This open CMT genetics data resource will allow for aggregation, archiving, analysis, comparison and sharing of genetic data among many laboratories and institutions. The resource could speed CMT research from gene identification to therapy discovery and development.

Making such data available to CMT researchers in the United States and around the world, could improve diagnostic processes, guide functional studies and drug discovery, and build the foundation for the patient selection process necessary for well-designed clinical trials.