@article{a74d50ced9a44e59ba4030e45e49df15,
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.",
author = "Leachman, {Sancy A.} and Hickerson, {Robyn P.} and Schwartz, {Mary E.} and Bullough, {Emily E.} and Hutcherson, {Stephen L.} and Boucher, {Kenneth M.} and Hansen, {C. David} and Eliason, {Mark J.} and Srivatsa, {G. Susan} and Kornbrust, {Douglas J.} and Smith, {Frances J.D.} and McLean, {Wh Irwin} and Milstone, {Leonard M.} and Kaspar, {Roger L.}",
note = "Funding Information: We are indebted to the pachyonychia congenita (PC) patient that made this study possible, as well as PC Project and the membership of the International Pachyonychia Congenita Consortium for their unfailing enthusiasm and support. We thank Manuel Flores for assistance with preparation of figures and Kristina Heintz for her nursing support. We also acknowledge financial sponsorship of the clinical trial by PC Project and FDA (US Food and Drug Administration) OOPD (Office of Orphan Products Development) grant 1-R01-FD-003553-01 (to S.A.L.). This work was further supported by NIH (National Institutes of Health) grant 1R43ARO56559 (to R.L.K.), a fellowship grant from PC Project (to F.J.D.S.), and by grants to W.H.I.M. and F.J.D.S. from the Dystrophic Epidermolysis Bullosa Research Association, the UK Medical Research Council (G0700314), and the British Skin Foundation. S.A.L. accepts full responsibility for the data presented in this manuscript. R.L.K., R.P.H., F.J.D.S., and W.H.I.M. have filed patents relating to short-interfering RNA therapy for PC. We thank Huntsman Cancer Institute for the use of clinical facilities for this trial. This work was completed in Salt Lake City, UT.",
year = "2010",
month = feb,
doi = "10.1038/mt.2009.273",
language = "English (US)",
volume = "18",
pages = "442--446",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "2",
}