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- Title
First-in-human Mutation-targeted siRNA Phase Ib Trial of an Inherited Skin Disorder.
- Authors
Leachman, Sancy A.; Hickerson, Robyn P.; Schwartz, Mary E.; Bullough, Emily E.; Hutcherson, Stephen L.; Boucher, Kenneth M.; Hansen, C. David; Eliason, Mark J.; Srivatsa, G. Susan; Kornbrust, Douglas J.; Smith, Frances J. D.; McLean, W. H. Irwin; Milstone, Leonard M.; Kaspar, RogerX L.
- 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.
- Subjects
SKIN diseases; RNA; GENETIC disorders; CLINICAL trials; MEDICAL genetics
- Publication
Molecular Therapy, 2010, Vol 18, Issue 2, p442
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1038/mt.2009.273