A Skin Cream For Peripheral Neuropathy?

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BOSTON — 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.

Kristian Hedstrom, PhD, and Joshua Murtie, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s are co-first authors of the study.

Funders include the National Institute of Neurological Disorders and Stroke (NINDS; R01 NS35884), the NIH Development Disability Research Center (P30-HD 18655), a
National Multiple Sclerosis Society Postdoctoral Fellowship, a Developmental Neurology Training Grant (T32NS007473) and the Technology Development Fund of the
Technology and Innovation Development Office (TIDO) at Boston Children’s. For information on business opportunities, read more on TIDO’s website or contact
[email protected]

Boston Children’s Hospital is home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children
and adults since 1869. More than 1,100 scientists, including seven members of the National Academy of Sciences, 13 members of the Institute of Medicine and 14 members of the Howard Hughes Medical Institute comprise Boston Children’s research community. Founded as a 20-bed hospital for children, Boston Children’s today is a
395-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and
diversity of children and families. Boston Children’s is also the primary pediatric teaching affiliate of Harvard Medical School. For more information about research
and clinical innovation at Boston Children’s, visit: http://vectorblog.org.

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Meghan Weber, Boston Children’s Hospital


[email protected]

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