It seems like every other day we hear about a new drug that has been approved for a rare neurologic disease. Increased understanding of the genetics underlying these diseases has led to numerous new gene therapies. Why have we not yet seen similar successes in CMT?

In order to answer this question, we must understand how CMT is different from these other rare neurologic diseases. There are two main barriers to rapid drug discovery and development in CMT:

• Heterogeneity: Unlike many other genetic disorders, CMT is not the result of a single genetic mutation. Rather, many different genetic mutations can disrupt the functioning of the peripheral nerves, the wires that transmit sensory signals from the skin to the brain and motor signals from the brain to the muscles. Over time, individual peripheral nerves wither away, a process called axonal degeneration, which leads to the lack of sensation and balance problems and muscle weakness that characterize CMT. To date, we have identified over 300 mutations in 100+ genes (and counting) that result in CMT. Developing gene therapies for every single mutation would take several decades, given that it traditionally takes roughly 10 years to develop a drug all the way to an approved treatment.
• Slow progression of disease: For most CMT patients, the disease progression is slow. Consequently, traditional ways of assessing disease progression, such as nerve conduction studies, show little change over time. Even clinic assessments that capture physical decline often take years to show a significant change in a patient’s functional ability. This means that therapies that are potentially effective could take many years to show a positive effect, especially if we use these slow-changing assessments in the trial. Problematically, most clinical trials only run for 1-2 years.

The CMT research community has attempted to address these challenges. To address the issue of heterogeneityin CMT, clinical trials to date have focused on the most common CMT mutations, such as the PMP22 gene duplication that causes CMT1A, the largest CMT population.  This approach has led to at least one successful global trial, the Pharnext trial in adult CMT1A, which is now awaiting a final decision from the FDA after they review safety and effectiveness data.

High throughput screens are another attempt to speed up the process of drug discovery for specific mutations.  However, these solutions would still only deliver therapies for individual mutations. An alternate approach might be to identify drugs that target the common endpoint of all CMT mutations, such as axonal degeneration, or muscle loss. This approach has the potential to impact many CMT mutations with one treatment. On the other hand, we must bear in mind that axonal degeneration and muscle loss are late stages of the disease; treatments targeting axonal degeneration or muscle loss may at best stabilize the disease, while treatments that target the genetic origins would have a better chance of altering the disease course entirely. It is also possible that a multiple-target approach might be needed, where we develop different drugs, from very targeted gene therapies to much broader process stabilizers, to target different aspects of the disease in a CMT patient.

To address the impasse of the slow progression of CMT, a tremendous amount of work has gone into identifying assessments that can detect the earliest and smallest change in the disease, such as assessing changes in fat fraction in the muscle by MRI, or the CMT Functional Outcome Measure that is currently being validated at leading CMT centers of excellence globally. The hope is that one of these assessments will be able to detect an early signal of improvement in a 1-year clinical trial, which, over years, will translate to improved function for CMT patients. Of note, a limitation of the measures being developed at present is that a patient is still required to go to a leading CMT center of excellence to get these specialized tests done, which can be inconvenient. Given that the physical decline that CMT patients experience is quite tangible at home, in their day-to-day lives, surely there must be a way to measure and access decline at home, so that a trip to a far-away center is not required? This has to be the way of the future: home-based or ‘virtual trials’, where patients are assessed at home, by video capturing a physical function or by questionnaires assessing their daily activities, and those assessments are relayed to a central monitoring site to determine if a treatment was effective based on the change in those assessments.

While it may seem that the pace of discovery has been slow, these are exciting times for the CMT community. Major research efforts by academia, CMT patient advocacy groups and industry are rapidly advancing the pace of research. Academic groups, like the Inherited Neuropathies Consortium, have united to develop critical outcome measures and concentrate their research on the most promising targets.  CMT patient advocacy groups, like the CMT Research Foundation*, partner with academia and industry to fund high-impact research projects which drastically move the needle on drug development. And, with the help of the researchers and patients, sectors of the pharmaceutical industry are developing a keen interest in delivering treatments for CMT.

There is a reason to hope!  We are closer than ever to not just alleviating the symptoms of the disease but eradicating it for good.  It will take a continued concentrated and collaborative effort coupled with significant investments from the patient community and pharmaceutical industry, but the CMT community has a reason to believe that treatments are eminent.

By Dr. Sindhu Ramchandren

*Dr. Ramchandren is a member of the CMT Research Foundation’s Scientific Advisory Board