title: First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder.
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.
authors: Department of Dermatology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-5550, USA. sancy.leachman@hci.utah.edu
authors: Sancy A
authors: SA
authors: Leachman
authors: Robyn P
authors: RP
authors: Hickerson
authors: Mary E
authors: ME
authors: Schwartz
authors: Emily E
authors: EE
authors: Bullough
authors: Stephen L
authors: SL
authors: Hutcherson
authors: Kenneth M
authors: KM
authors: Boucher
authors: C David
authors: CD
authors: Hansen
authors: Mark J
authors: MJ
authors: Eliason
authors: G Susan
authors: GS
authors: Srivatsa
authors: Douglas J
authors: DJ
authors: Kornbrust
authors: Frances Jd
authors: FJ
authors: Smith
authors: Wh Irwin
authors: WI
authors: McLean
authors: Leonard M
authors: LM
authors: Milstone
authors: Roger L
authors: RL
authors: Kaspar
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D009154:Mutation / Q000235:genetics; D053549:Pachyonychia Congenita / Q000235:genetics / Q000628:therapy; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D012871:Skin Diseases / Q000235:genetics / Q000628:therapy*
chemical_list: D034741:RNA, Small Interfering