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Clinical Trial
. 2010 Feb;18(2):442-6.
doi: 10.1038/mt.2009.273. Epub 2009 Nov 24.

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

Sancy A Leachman  1 , 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 Jd Smith, Wh Irwin McLean, Leonard M Milstone, Roger L Kaspar
Affiliations
Clinical Trial

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

Sancy A Leachman et al. Mol Ther. 2010 Feb.

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.

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Figures

<b>Figure 1</b>
Figure 1
Patient assessment demonstrates subjective improvement in the right foot (TD101, blue) but not the left foot (vehicle, red) as determined by daily diary entries. Note that the scores for the left foot have been slightly offset so that the left and right foot scores do not overlap at baseline. The improvement scores and a curve fit through the scores are both plotted. The corresponding dose (gray) is indicated by a separate graph. An improvement score of 10 represents “definitely not working,” whereas a score of 0 represents “definitely working.” The improvement returns to baseline after treatment is completed.
<b>Figure 2</b>
Figure 2
The length of the callus on the right foot (TD101, blue), but not the left foot (vehicle, red), decreased significantly during the dosing period (day 0 to day 118) (drug versus vehicle, P = 0.004). The measured callus length (dots and open circles) and a piecewise linear fit through the callus lengths are both plotted (see Materials and Methods). The fit has a change in slope at the end of the dosing period. The corresponding dose is indicated by a separate graph.
<b>Figure 3</b>
Figure 3
Improvement of pachyonychia congenita symptoms following TD101 administration. Callus regression is seen on the right foot at the site of injection of (a) TD101 (center arrow), but not at the site of injection of (b) vehicle on the left foot (arrows). Note that relative to the first injection, the callus on the right foot (but not on the left) developed a clearing of callus around the site of injection. The third photo in each panel is an enlargement of the site of injection from the day 115 photos. The callus on the right foot also shows some regression near the instep of the foot resulting in a shortening of the total callus length.
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