Researchers at Boston Children’s Hospital have developed a skin cream that may relieve a difficult-to-treat form of peripheral neuropathy that is common in people with diabetes and affects millions of people in the U.S. As reported in this week’s edition of the Proceedings of the National Academy of Sciences, the topical cream tested well in two mouse models of small-fiber neuropathy.
Small-fiber neuropathy, affecting millions of people in the U.S., causes pain, tingling and the loss of sensation, usually starting in the feet. Loss of sensation in the feet can increase the chances of ulcers and infections that may lead to amputation, a well-known problem in diabetes. Small-fiber neuropathy also can result from other autoimmune diseases, HIV infection and chemotherapy treatment. Current treatments consist of analgesics to reduce pain, but these cause unwanted side effects, do not restore sensation and do not address the underlying cause of the neuropathy.
Because small-fiber neuropathy is known to degenerate the nerve endings of sensory neurons and the loss of a group of factors stimulating nerve growth (GNDF), Gabriel Corfas, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s, wondered if replenishing GDNF could improve sensory neurons’ health and function.
“Other investigators have been testing the potential use of GDNF in neuropathy, but since GDNF is a large molecule, the only way to get it into the nervous system is through invasive methods such as injections into the spinal cord,” says Corfas.
Thus, rather than using GDNF itself, Corfas and colleagues created a skin cream containing a small-molecule compound, called XIB4035, which enhances GDNF’s effects. “When you use an enhancer, you need less GDNF to activate receptors on the sensory neuron,” Corfas explains. “The receptors are activated for longer, and GDNF’s effects are stronger.”
When mice with small-fiber neuropathy were given the skin cream, they showed improvements in nerve structure and regained sensitivity to heat in their paws as compared with controls receiving an inactive cream. Sensation improved in both diabetic mice and mice that developed small-fiber neuropathy through genetic manipulation. Even mice with advanced disease showed improvements.
“People have been able to treat pain in small-fiber neuropathy, but the treatments cause side effects, and there’s nothing that can help the loss of sensation, which can contribute to people losing limbs,” Corfas says.
The study offers hope for a more targeted, practical treatment for small-fiber neuropathy, says Corfas. “By giving an enhancer, you help only the cells that naturally are exposed to the growth factors and that have the receptors for them,” he says. “Also, because the enhancer is given topically, we are effectively putting it into the neurons, which have their endings in the skin. So there is very little systemic exposure, and we believe there will be far fewer side effects.”
The team is now examining whether the cream has any value for large-fiber neuropathy, which involves motor fibers and is often caused by injury. They also will further explore skin absorption of XIB4035, as well as the effects of systemic delivery.
(Source: Boston Children’s Hospital)