Treating small fiber neuropathy by topical application of a small molecule modulator of ligand-induced GFRα/RET receptor signaling.
Small-fiber neuropathy (SFN) is a disorder of peripheral nerves commonly found in patients with diabetes mellitus, HIV infection, and those receiving chemotherapy. The complexity of disease etiology has led to a scarcity of effective treatments. Using two models of progressive SFN, we show that overexpression of glial cell line-derived neurotrophic factor (GDNF) in skin keratinocytes or topical application of XIB4035, a reported nonpeptidyl agonist of GDNF receptor α1 (GFRα1), are effective treatments for SFN. We also demonstrate that XIB4035 is not a GFRα1 agonist, but rather it enhances GFRα family receptor signaling in conjunction with ligand stimulation. Taken together, our results indicate that topical application of GFRα/RET receptor signaling modulators may be a unique therapy for SFN, and we have identified XIB4035 as a candidate therapeutic agent.
F. M. Kirby Neurobiology Center, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115.
Kristian L
KL
Hedstrom
Joshua C
JC
Murtie
Kathryn
K
Albers
Nigel A
NA
Calcutt
Gabriel
G
Corfas
D000287:Administration, Topical; D000818:Animals; D004916:Erythromelalgia / Q000188:drug therapy*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D011804:Quinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D015398:Signal Transduction; D054852:Small Molecule Libraries
C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; D011804:Quinolines; D054852:Small Molecule Libraries; C470912:XIB 4035; D051096:Proto-Oncogene Proteins c-ret
pain; sensory; thermonociception; topical drug; trophic factor