期刊
MOLECULAR THERAPY
卷 18, 期 2, 页码 442-446出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2009.273
关键词
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资金
- PC Project and FDA (US Food and Drug Administration) OOPD (Office of Orphan Products Development) [1-R01-FD-003553-01]
- NIH (National Institutes of Health) [1R43ARO56559]
- Dystrophic Epidermolysis Bullosa Research Association
- UK Medical Research Council [G0700314]
- British Skin Foundation
- MRC [G0700314, G0801742, G0802780] Funding Source: UKRI
- Medical Research Council [G0802780, G0700314, G0801742] Funding Source: researchfish
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.
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