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Mol Ther. 2010 Feb;18(2):442-6. doi: 10.1038/mt.2009.273. Epub 2009 Nov 24.

First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder.

Author information

1
Department of Dermatology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-5550, USA. sancy.leachman@hci.utah.edu

Abstract

The rare skin disorder pachyonychia congenita (PC) is an autosomal dominant syndrome that includes a disabling plantar keratoderma for which no satisfactory treatment is currently available. We have completed a phase Ib clinical trial for treatment of PC utilizing the first short-interfering RNA (siRNA)-based therapeutic for skin. This siRNA, called TD101, specifically and potently targets the keratin 6a (K6a) N171K mutant mRNA without affecting wild-type K6a mRNA. The safety and efficacy of TD101 was tested in a single-patient 17-week, prospective, double-blind, split-body, vehicle-controlled, dose-escalation trial. Randomly assigned solutions of TD101 or vehicle control were injected in symmetric plantar calluses on opposite feet. No adverse events occurred during the trial or in the 3-month washout period. Subjective patient assessment and physician clinical efficacy measures revealed regression of callus on the siRNA-treated, but not on the vehicle-treated foot. This trial represents the first time that siRNA has been used in a clinical setting to target a mutant gene or a genetic disorder, and the first use of siRNA in human skin. The callus regression seen on the patient's siRNA-treated foot appears sufficiently promising to warrant additional studies of siRNA in this and other dominant-negative skin diseases.

PMID:
19935778
PMCID:
PMC2839285
DOI:
10.1038/mt.2009.273
[Indexed for MEDLINE]
Free PMC Article

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