About half of people with diabetes develop peripheral neuropathy. The most common form, small-fiber neuropathy, generally starts in the feet, causing pain, odd sensations like pricks and “pins and needles,” and—the most worrisome feature—a loss of sensation that can increase the chance of ulcers and infections.

In some cases, that may lead to the need for amputation—as happened with my diabetic great-grandfather whose numbed feet, unbeknownst to him, got too close to the fire.

While there are some treatments to reduce pain, there’s nothing that restores sensation. Nor do any existing treatments address the underlying cause of the neuropathy: the degeneration or dysfunction of the endings of the sensory neurons in the skin.

Gabriel Corfas, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, wondered if replenishing a growth factor called GDNF (short for glial-derived neurotrophic factor) could improve sensory neurons’ health and function. Other investigators have been testing this, but because GDNF is a large molecule, it’s hard to deliver. “The only way to get it into the nervous system is through invasive methods such as injections into the spinal cord,” says Corfas.

Because the sensory nerve endings are in the skin, Corfas felt it might be possible to treat neuropathy topically, a gentler treatment that would avoid the side effects of systemic treatments. He turned not to GDNF, which is too large to be absorbed through the skin, but to a small-molecule compound called XIB4035 that enhances GDNF’s effects—making the little that’s there go a longer way.

“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.”

In last week’s edition of the Proceedings of the National Academy of Sciences, his team reports good results with a skin cream laced with XIB4035 in two mouse models of small-fiber neuropathy.

As compared with controls given an inactive cream, mice given the XIB4035 skin cream showed improvements in nerve structure and regained sensitivity to heat (much more quickly removing their paws from a hot plate). Sensation improved in both diabetic mice and mice that developed small-fiber neuropathy through genetic manipulation. Even mice with advanced disease showed improvements.

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 are naturally exposed to the growth factors and have the receptors for them,” he says. “Also, because the enhancer is given topically, we are effectively putting it directly 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.

The cream is still experimental, Corfas cautions, and years away from human testing. He elaborates on the cream in this Q&A with Boston Children’s Technology & Innovation Development Office (TIDO), which provided financial support for the project. For information on business opportunities, read more on TIDO’s website or contact connie.caron@childrens.harvard.edu.