Peripheral Neuropathy Reversed in Zebrafish After Treatment with 2 Drugs

A researcher has identified two drugs that may be used to reverse peripheral nerve damage, also referred to as peripheral neuropathy, resulting from diseases like multiple sclerosis (MS) and diabetes, the use of chemotherapy in the treatment of some cancers, or traumatic injuries. The researcher, Sandra Rieger, PhD, is an assistant professor at the  Mount Desert Island (MDI) Biological Laboratory in Maine.

The two drugs, not specified in a press release, are under a provisional patent filed this month by MDI Biological Laboratory. Dr. Rieger will continue her work through Novo Biosciences, MDI’s for-profit spinoff company, to advance the drugs into clinical trials. If these drugs demonstrate efficacy in treating nerve damage, they will be further licensed to a pharmaceutical for further trials, with the ultimate goal of obtaining U.S. Food and Drug Administration approval.

“Currently, there are no effective treatments for the underlying causes of peripheral neuropathy, which affects 30 to 40 percent of chemotherapy patients,” Kevin Strange, PhD, the president of the laboratory, said in the release. “Our hope is that Dr. Rieger’s work in the zebrafish model will lead to an effective treatment for this condition, which can cause disabling difficulty in carrying out everyday activities such as walking, writing, getting dressed and handling small objects.”

Dr. Rieger found that in the presence of the chemotherapy agent paclitaxel, peripheral neuropathy is triggered by the increased expression of MMP13 (matrix metallopeptidase 13), a gene that encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this family are involved in the breakdown of the extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. MMP-13 is toxic to nerves and degrades collagen, increasing the predisposition of the skin to injury from everyday stresses.

The increase in MMP-13 activity causes disruptions to the intricate interactions between the skin and nerves, which are thought to contribute to the nerve damage induced by paclitaxel. In her research, Dr. Rieger identified two drugs that prevent paclitaxel-induced neurotoxicity by decreasing MMP-13 activity, which may be a new opportunity for therapeutic interventions.

Dr. Rieger and colleagues at MDI’s Kathryn W. Davis Center for Regenerative Medicine found that zebrafish given both paclitaxel and the drugs did not suffer axon degeneration and showed a restored touch response. She is now working with the Mayo Clinic in Rochester, Minnesota, on studies in human skin tissue.

“Once we’ve completed our studies on mammalian models, we’d like to collaborate with a medical institution or pharmaceutical company on clinical trials in humans,” Dr. Rieger said. “The current thinking is that no single drug is likely to be effective for the treatment of all peripheral neuropathies, which can stem from multiple causes. The hope, however, is that these drugs can also be used to treat other neuropathies or that the zebrafish model can be used to identify novel candidates for the treatment of other neuropathies.”

Peripheral neuropathy (PN) results from damage to or disease affecting nerves, and may impair sensation, movement, gland or organ function, depending on the type of nerve affected. PN affects an estimated 8 million people in the U.S.