Q and A with Gabriel Corfas, PhD

A topical formulation may succeed in treating various peripheral neuropathies

Gabriel Corfas

Gabriel Corfas, PhD, a senior associate in Neurology and Otolaryngology at BCH and a professor of Neurology and Otology & Laryngology at HMS, has developed a topical formulation that may succeed in treating certain peripheral neuropathies. The disorders targeted by the therapy affect the peripheral nerves that connect the central nervous system to muscles, skin and internal organs, causing weakness, numbness, tingling and pain in the extremities. Twenty million people in Europe and the US suffer from peripheral neuropathy and there is no treatment other than alleviating symptoms.

Dr. Corfas discovered his therapeutic while studying the interactions between axons in peripheral nerves and their associated supporting cells. Through this research, he found a small molecule that when applied to the skin can prevent and reverse the nerve damage underlying the pathophysiology of neuropathy.

In this interview, Dr. Corfas talked to the Technology and Innovation Development Office (TIDO) about how his discovery came about, why it has the potential to cure neuropathy, and what his plans are for the future development of this technology.

TIDO: Tell me about your neuropathy treatment.

Dr. Corfas: As you know, peripheral neuropathies affect millions of people. Current treatments for peripheral neuropathies do not cure the disease, but are rather palliative, dealing only with symptoms. In animal models, we have been able to cure some peripheral neuropathies with a cream containing a small molecule that enhances signaling by proteins belonging to a family of neurotrophic factors called the GDNF family (for Glial-Derived Neurotrophic Factor). We believe that this approach could help prevent the development of neuropathies in people who are predisposed to these disorders and also help people that already have the disease.

TIDO: How did the discovery come about?

Dr. Corfas: We were investigating the mechanisms that mediate the interactions between peripheral nerve axons and the non-neuronal cells that surround them. These cells, called Schwann cells (one of several different nervous system cells called glia), are believed to provide support to neurons, but the mechanisms by which they do so are unclear. To begin to define these mechanisms we investigated a molecule we believe is important for axon-Schwann cell interactions, and generated transgenic mice in which the function of this molecule is blocked specifically in the Schwann cells. We found that these mice develop a severe peripheral neuropathy that involves the degeneration of axons and the inability to feel thermal pain. While looking for the mechanisms that caused the neuropathy in this mouse model, we found that the levels of a molecule named GDNF were dramatically reduced in the nerves of the sick mice. To test if the reduction of GDNF could be the cause of the neuropathy, we bred the mutant mice with mice that have extra GDNF in the skin. The results were remarkable. In the offspring of these crosses, the symptoms were absent—presumably thanks to the extra GDNF in the skin. Based on these observations, we hypothesize that neuropathies can be treated by applying molecules that mimic GDNF directly onto to the skin.

TIDO: So is this why you decided to deliver the compound topically?

Dr. Corfas: Other investigators have been testing the potential use of GDNF for this type of disorder. However, since GDNF is a large molecule that does not penetrate the skin, the only way this can be achieved is by introducing this protein into the nervous system by invasive methods such as injections into the spinal cord. Our experiment suggested that if we can apply a small GDNF-like molecule to the skin, it might be sufficient to repair the whole nerve. Indeed, we identified a small molecule that was reported to be a mimic of GDNF, prepared it in cream-form and found that it is very effective in treating the neuropathy in the mouse models. However, when we looked at the mechanism of action of this small molecule in greater detail, we discovered it is not GDNF mimetic as previously reported, but rather a positive modulator that enhances ligand-induced signaling by all the member of the GDNF family of trophic factors. This was an important insight because different sensory neurons express different types of receptors and respond to different GDNF family members, suggesting that the small molecule has a broader spectrum of therapeutic action. Another advantage of using a positive modulator is that it is likely to have much less side effects than a trophic factor, as it will not activate a signaling pathway in cells that are not normally exposed to the ligand, but only enhance it where all the natural endogenous components (ligands and receptors) are present.

TIDO: What is the current treatment for neuropathy and what makes this better?

Dr. Corfas: As I mentioned previously, current treatments for neuropathies deals with symptoms, for example pain, or with the underlying disorders that can cause the nerve problems, like diabetes, but there are no tools currently to treat, repair or stop the neuropathy directly. And even when diabetes is treated or controlled, the neuropathy remains because the nerves are already damaged. There are other groups that are using the same family of signaling pathways in thinking about neuropathy, but they are using these invasive systemic approaches rather than a topical, small molecule application.

TIDO: Why has it taken so long to find a treatment for this disease?

Dr. Corfas: That is something really intriguing. It may be because it is a pathology that can be caused by many different conditions. For example, diabetes, chemotherapy and injury can all contribute to neuropathy, but each appears to do it via different mechanisms. Given our experimental results, we may be able to help people suffering from different kinds of neuropathy by using this technology that addresses the basic cellular mechanisms responsible for preserving and possibly repairing the function of axons.

TIDO: How has TIDO and the Technology Development Fund helped further your findings?

Dr. Corfas: TIDO has been a great partner in this effort. We have the expertise and resources in our lab to design and execute many experiments, but TIDO has been instrumental in bringing our discoveries to the next phase of development. Through TIDO, we have had the opportunity to connect to people working in industry, and we have been able to explore the possibility of collaborating with groups to bring this technology into the pharmaceutical realm. They have been an important component of our work.

TIDO has also been creative in generating resources to develop projects. These projects are not easy to fund with traditional funding mechanisms, such as those from the NIH. TIDO provided crucial seed money to push this technology forward. More recently, with the Technology Development Fund, we have been able to work with a CRO to get insights into the aspects of this molecule that are important when considering its use on humans.

TIDO: What research and development work are you currently conducting?

Dr. Corfas: We are studying many properties of the molecule, for example its stability as a pharmaceutical product, its compatibility with excipients, whether it is permeable in membranes, and its pharmacokenetics and pharmacodynamics in animal models. This information is vital to understanding how this drug can be used for treatments.

TIDO: How would you describe your personal connection to this technology?

Dr. Corfas: I consider myself a basic neuroscientist. I have been interested in how the brain works, what molecules regulate its functions and what the roles of glia are. However, I have always believed that if we understand these basic mechanisms, we will be able to develop cures for many diseases. This technology gives me the satisfaction of seeing that model work. By researching the question of how cells communicate with each other in peripheral nerves, we discovered potential mechanisms of disease and potential ways to treat them. I would be very excited to see our basic research develop into a discovery that can improve the lives of many people.

This neuropathy technology is available for licensing

Related Links

  1. Gabriel Corfas, PhD
  2. The Corfas Laboratory
  3. Profile: Neuroscience at Boston Children's Hospital
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  5. Novel pathway regulates timing of brain-cell development
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