Study Identifies Mechanism Underlying a Form of Sensory Nerve Damage

Researchers have discovered a mechanism that underlies induction of peripheral neuropathy (PN) by the chemotherapeutic agent paclitaxel, raising the prospects for developing treatments for this and possibly also for certain other forms of PN. The work may also lead to companion diagnostics to identify patients who would benefit from these new therapies.

The study was led by Sandra Rieger, PhD, of Mount Desert Island Biological Laboratory (Bar Harbor, ME, USA). "Our goal is to develop treatments that activate the repair and regeneration of damaged tissues," said Kevin Strange, PhD, president, MDI Biological Laboratory, "Sandra Rieger's research has advanced that mission.”

Peripheral nerve damage is a common condition (e.g. ~8 million people are affected in the US) that causes increasing pain and numbness and/or tingling in the hands and/or feet. Lack of understanding of underlying mechanisms has held back development of treatments. Drugs exist for the treatment of symptoms (e.g. pain relievers), but not for the condition itself, which can be caused by chemotherapy, diabetes, traumatic injury, heredity, and other conditions.

"The general thinking is that no single drug can be effective for the treatment of all PNs, which stem from multiple causes," said Dr. Rieger, "But our research indicates that there may potentially be a common underlying mechanism for some neuropathies affecting the sensory nervous system that could be manipulated with drugs targeting a single enzyme."

Dr.Rieger and other scientists at the institution's Davis Center for Regenerative Medicine study tissue repair, regeneration, and aging in a diverse range of organisms that have robust mechanisms to repair and regenerate lost and damaged tissues. In the new study, zebrafish were exposed to paclitaxel, used to treat ovarian, breast, lung, pancreatic, and other cancers. Paclitaxel-induced PN affects the majority of treated patients; however, those who are most severely affected (~30%) have to terminate chemotherapy early or reduce the dose, which may hinder cancer survival.

The researchers developed a larval zebrafish model of PN because the embryos develop rapidly and larval fish are translucent, ideal for studying progression of nerve degeneration in live animals. The results showed that paclitaxel induced degeneration of sensory nerve endings by damaging the epidermis (outer layer of skin), which is innervated by free sensory nerve endings that establish direct contact with skin cells. The degeneration was determined to be caused by perturbations in the epidermis due to an increase in the enzyme matrix-metalloproteinase 13 (MMP-13), which degrades the collagen between the cells. Increased MMP-13 activity may be triggered by oxidative stress, a hallmark of diabetic PN.

The zebrafish were treated with pharmacological agents that reduce MMP-13 activity, with the result that skin defects were improved and chemotherapy-induced nerve damage was reversed. Additional research will focus on effect of MMP-13 on PN in mammalian models. Studies are also underway in collaboration with Mayo Clinic (Rochester, MN, USA) to test the clinical relevance of these findings in humans. PN treatment using MMP-13- targeting compounds is now the subject of a provisional patent by MDI Biological Laboratory.

MMP-13 over-activation has also been linked to other disease conditions, including tendon injury, intestinal inflammatory, and cancer, suggesting that drugs developed to treat PN may yield other health benefits as well.

The study, by Lisse TS et al, was published March 28, 2016, in the journal Proceedings of the National Academy of Sciences.

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Mount Desert Island Biological Laboratory