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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.

SUBMITTER: Leachman SA

PROVIDER: S-EPMC2839285 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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

Leachman Sancy A SA Hickerson Robyn P RP Schwartz Mary E ME Bullough Emily E EE Hutcherson Stephen L SL Boucher Kenneth M KM Hansen C David CD Eliason Mark J MJ Srivatsa G Susan GS Kornbrust Douglas J DJ Smith Frances Jd FJ McLean Wh Irwin WI Milstone Leonard M LM Kaspar Roger L RL

Molecular therapy : the journal of the American Society of Gene Therapy 20091124 2

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 TD1 ...[more]

PMID: 19935778

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Dataset Information

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

Publications

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

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