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Five Questions with CMT Researchers Robert Burgess and Scott Harper

Robert W. Burgess, a professor at The Jackson Laboratory in Bar Harbor, Maine, is conducting MDA-funded research that may lead to a new therapy for Charcot-Marie-Tooth disease (CMT). With co-investigator Scott Q. Harper, associate professor at Nationwide Children’s Hospital Center for Gene Therapy in Columbus, Ohio, Burgess is testing an AAV gene therapy approach to specifically block the altered form of the GARS gene in a newly developed mouse model for the type 2D form of CMT.

Please describe your current research.

Charcot-Marie-Tooth disease comprises a group of inherited peripheral neuropathies that result in muscle weakness and sensory deficits, particularly in the hands and feet.  Collectively these diseases occur in about 1:2,500 people, but any given genetic form of CMT may be quite rare. Although CMT can be debilitating and require lifelong care, there are no treatments for CMT besides supportive measures.

Using mouse models of one form, CMT type 2D, we are attempting proof-of-principle studies to show that gene therapy can be an effective treatment. We presently have three strains of mice that carry mutations in GARS, the CMT2D gene. These mice develop a neuropathy that very closely resembles the human disease. Furthermore, one of these mutations was engineered to recreate a human disease-associated mutation. Thus, we can use these mice in preclinical trials to determine if we can successfully treat CMT2D using gene therapy.

The mutations in patients and mice that cause CMT2D are dominant, meaning there is one normal copy and one mutant copy of the GARS gene present. An important consideration for our approach is that we need to reduce the mutant gene while minimally impacting the normal gene. Our preliminary data suggest that this should be possible with our gene therapy approach, and we are now ready to test this in our mouse models.

Successful completion of these experiments will represent the first gene therapy treatment for a dominant neuropathy mutation and will set the stage for further development of this approach for CMT2D and related disorders, leading to eventual trials in patients. Importantly, this project is a collaborative effort between Dr. Robert Burgess, who develops and studies mouse models of neuromuscular diseases, and Dr. Scott Harper, who develops gene therapy approaches and has the resources at Nationwide Children’s Hospital to bring these preclinical studies into clinical trials.

What inspired you to study CMT?

Patients with CMT suffer significant disability, but receive little of the attention that those with other neurodegenerative disorders receive. Furthermore, we have a longstanding interest in neuromuscular diseases, and CMT is an interesting disease for its many and varied biological mechanisms and an important area of study given the unmet clinical need. We have found particular traction with CMT2D because of the excellent mouse models available.

What is your focus within the CMT field?

We are interested in developing mouse models of CMT and related neuromuscular disorders, and using these mice to explore disease mechanisms and as preclinical models for testing therapeutic approaches.

There are currently no effective treatments for CMT, and its varied genetic causes and small patient populations make it an unattractive area for conventional drug development. However, these same factors make it an excellent disease for treatment through personalized genetic approaches. Our proof-of-concept studies in mouse models will provide a very important first step in establishing the effectiveness of these approaches.

Does your work have any potential implications for other disease fields?

Our gene therapy approach, “allele-specific inhibition by RNAi,” could potentially be applied to many dominant neuromuscular diseases, including many types of CMT and even motor neuron diseases such as amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease).

What do you feel people impacted by CMT can have the most hope about with respect to research right now?

There are currently no effective treatments for CMT, and while there are many steps to clinical trials in patients, the successful completion of our project would be a major step towards establishing gene therapy as an effective strategy for treating CMT.

We will investigate whether our strategy can effectively reverse the neuropathy after its onset, but we also hope that we can prevent the disease by treating before the onset, which offers great promise for screening and treating children in families known to carry CMT before the symptoms start.

Why is it important that MDA continue to fund research in CMT?

CMT is often called “The most common disease you have never heard of.” It receives little attention for conventional drug development because of the lack of clear disease mechanisms and relatively small patient populations, particularly for rarer genetic forms. Therefore, the development of treatments largely depends on the efforts of independent investigators funded by organizations such as MDA, which is currently the only major foundation funding such work.