5 Questions for Joshua Burns, PhD

This question-and-answer series explores the motivations, inspirations and accomplishments of investigators at St. Jude. Joshua Burns, PhD, is the St. Jude Disability Prevention Program director, Human Performance, Gait & Mobility Labs director and Department of Epidemiology & Cancer Control member.

1. What led you to a career in researching pediatric neuropathies?

My clinical training was in podiatry, which is all about assessing and understanding foot problems. During my PhD training in biomechanics, I encountered many patients with neuromuscular diseases that have significant foot deformities, such as Charcot-Marie-Tooth disease (CMT). They experienced chronic pain, difficulty standing for long periods and frequent trips and falls.

While I started as a foot-focused researcher, I was inspired by my supervisors and mentors to become more interested in the neurogenetic condition and learn more about how we could help these people. I wanted to know how we measure and manage the broad range of difficulties this disabling disease produces. Since then, my major contribution to the field has been developing and validating outcome measures for disease-modifying therapies, so we can assess their effectiveness in clinical trials.

Over the last two decades, I’ve gone from working as a podiatrist focused on a symptom in the foot to now trying to help treat the whole condition.

2. You recently published an article describing Charcot-Marie-Tooth disease extensively in Nature Reviews Disease Primers. Briefly, what is CMT?

CMT is an inherited peripheral neuropathy, affecting about one in 2,500 globally, meaning hundreds of thousands of people are currently impacted. It’s a monogenic problem, an inherited disease caused by a mutation in a single gene. So far, we’ve documented more than 130 genetic subtypes, all with a different particular genetic cause resulting in slightly different versions of the disease.

The most common form, CMT type 1A, is caused by a duplication of the gene PMP22 on chromosome 17. In CMT1A, peripheral nerves demyelinate, meaning the outer coatings surrounding the nerve axons deteriorate over time. Subsequently, the long extensions from neurons that send signals to other neurons or muscles, known as axons, degrade. Those losses lead to muscle weakness, sensory loss and profound problems with gait and function. CMT manifests itself first in a “stocking and glove pattern,” which means it affects the hands and feet first; then, over time, the damage extends closer to the trunk of the body, eventually causing problems everywhere.

3.  What are the major challenges for patients with CMT disease?

CMT appears at different ages based on which mutations a person has. Generally, we see children as young as 3 or 4 years of age affected by the disease. So, in the first few years, very few subtypes reveal themselves without genetic testing. Instead, we see 4- or 5-year-olds experiencing trips and falls, clumsiness and unsteadiness. We then take a closer look, and we’ll see problems with the neurological system, such as absent tendon reflexes and not feeling a pin-prick sensation, starting in the hands and feet. Certain subtypes do not manifest until adolescence but will have similar symptoms.

Over time, we see patients experience a slow disease progression into adulthood. Physically, it continues to weaken the muscles and cause balance and sensory loss. Foot and hand deformities are also common. Thankfully, few subtypes decrease lifespan, and those are the subtypes for which many of the current drug therapies are being developed.

However, there is a high socioemotional cost to the disease. The challenges of CMT have negative effects on patients’ ability to work, make and maintain friendships, and place a large burden on their mental health.

4. What kind of research are you doing to better understand the disease and find better treatments?

Over my career, I’ve helped lead studies that have collectively included over 10,000 patients with CMT. When I began, there were several clinical trials running simultaneously, but each of us was using a different outcome measure. Some measured grip strength, some measured balance and some measured nerve conduction velocity, but there was no standard, which caused issues with proving efficacy and gaining regulatory approvals.

I received a Fulbright Postdoctoral Scholarship in Neurogenetics to work on the disease and better coordinate globally how we conduct clinical trials for CMT. We did many natural history studies, following thousands of patients over many years to see the normal progression of the disease, which helps us design trials and get pharmaceutical companies interested in participating. We then developed the scales that are used to evaluate endpoints in all these trials, advising on many, including several major disease-modifying strategies ongoing today.

Currently, I collaborate with the Pediatric Translational Neuroscience Initiative, which was started at St. Jude several years ago to address neurologic diseases. I was recruited here, along with my colleague Richard Finkel, MD, in part because we are two of the most published researchers on CMT and related neuropathies globally. We’re building out the program to lead new disease-modifying clinical trials, as well as participating in existing trials.

5. What changes would you like to see for CMT disease treatment going forward?

As a rare disease, many health centers are not well-equipped to treat patients with CMT. I hope that by providing published standards of care and generating user-friendly content, we can improve the general understanding and care for children and adults with CMT. We developed a website, www.ClinicalOutcomeMeasures.org, to provide assessment tools for free, including resources on how to use them correctly and how to best manage the disease.

With these tools, I’m trying to empower patients to go to providers and say, “Here’s the standard of care,” and have access to the outcome measures to use and the person who developed them in case they need more information. I’ve already seen a positive response from the CMT community.

One of my long-term and most exciting goals is to take what we’ve learned from CMT and apply it to patients with pediatric cancer and survivors of childhood cancer. Some children require amputation or limb salvage surgeries, which require similar measurement frameworks as CMT to see how the orthopedic surgery is going. We’d also like to get them into the Human Performance, Gait & Mobility Labs that I now run, to evaluate chemotherapy-induced peripheral neuropathy, and see what lessons can be shared between the two populations of patients with neuropathy.

Ultimately, for any child facing these neuropathies, we want to learn how to best go about disability prevention. In the case of CMT, we’ll continue pursuing disease-modifying therapies until we find a cure. That’s the future we’re working together to build.