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

TY - JOUR

T1 - First-in-human mutation-targeted siRNA Phase Ib trial of an inherited skin disorder

AU - Leachman, Sancy A.

AU - Hickerson, Robyn P.

AU - Schwartz, Mary E.

AU - Bullough, Emily E.

AU - Hutcherson, Stephen L.

AU - Boucher, Kenneth M.

AU - Hansen, C. David

AU - Eliason, Mark J.

AU - Srivatsa, G. Susan

AU - Kornbrust, Douglas J.

AU - Smith, Frances J. D.

AU - McLean, W. H. Irwin

AU - Milstone, Leonard M.

AU - Kaspar, Roger L.

PY - 2010/2

Y1 - 2010/2

N2 - 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.

AB - 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.

KW - INCLUDING PACHYONYCHIA-CONGENITA

KW - RNAI THERAPEUTICS

KW - MODEL

KW - DELIVERY

U2 - 10.1038/mt.2009.273

DO - 10.1038/mt.2009.273

M3 - Article

C2 - 19935778

SN - 1525-0016

VL - 18

SP - 442

EP - 446

JO - Molecular Therapy

JF - Molecular Therapy

IS - 2

ER -