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

Sancy A. Leachman, Robyn P. Hickerson, Mary E. Schwartz, Emily E. Bullough, Stephen L. Hutcherson, Kenneth M. Boucher, C. David Hansen, Mark J. Eliason, G. Susan Srivatsa, Douglas J. Kornbrust, Frances J.D. Smith, Wh Irwin McLean, Leonard M. Milstone, Roger L. Kaspar

Research output: Contribution to journalArticlepeer-review

234 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)442-446
Number of pages5
JournalMolecular Therapy
Issue number2
StatePublished - Feb 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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