GPR177 and WNT5A as targets for diabetic neuropathy

Blocking WNT5A or the Wnt transport protein GPR177, which facilitates WNT5A secretion by dorsal root ganglion neurons, could help treat diabetic neuropathy. WTN5A protein levels were more than ten-fold higher in cerebral spinal fluid from diabetic patients with neuropathic pain than from diabetic patients without pain, and protein abundance correlated with pain intensity.

In a chemically induced mouse model of diabetes, conditional knock out of GPR177 in sensory neurons prevented neuronal loss in the dorsal root ganglion and spinal cord, decreased mechanical allodynia and hyperexcitability of nociceptor neurons, and rescued the loss of intraepidermal nerve fibers compared with normal expression, while not impairing normal pain responses. Structure-based computational design yielded a peptide that disrupted the interaction between WNT5A and the nociceptor-specific ion channel TRPV1, and in diabetic mice, intrathecal administration of the peptide decreased mechanical allodynia compared with vehicle...