First-in-human Mutation-targeted siRNA Phase Ib Trial of an Inherited Skin Disorder
First-in-human Mutation-targeted siRNA Phase Ib Trial of an Inherited Skin Disorder
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DOI：
10.1038/mt.2009.273
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发表时间：
2010-02-01
影响因子：
12.4
通讯作者：
Kaspar, Roger L.
中科院分区：
文献类型：
--
作者：
Leachman, Sancy A.;Hickerson, Robyn P.;Kaspar, Roger L.
罕见的先天性厚甲癣（PC）是一种常染色体显性综合征，包括致残性足底角化病，目前尚无令人满意的治疗方法。我们已经完成了使用首个基于短干扰RNA （siRNA）的皮肤治疗方法治疗PC的Ib期临床试验。这种siRNA被称为TD101，它特异性且有效地靶向角蛋白6a (K6a) N171K突变mRNA，而不影响野生型K6a mRNA。TD101的安全性和有效性是在一项为期17周、前瞻性、双盲、分体、载体对照、剂量递增的单患者试验中进行的。将随机分配的TD101溶液或车辆对照注射到对侧脚对称的足底老茧中。试验期间或3个月洗脱期未发生不良事件。主观患者评估和医生临床疗效测量显示，sirna处理的足部有骨痂消退，而载体处理的足部没有。该试验是siRNA首次在临床环境中用于靶向突变基因或遗传疾病，也是siRNA首次在人体皮肤中使用。在患者的siRNA治疗足部上观察到的老茧消退似乎足够有希望在这种和其他显性阴性皮肤病中进行siRNA的进一步研究。
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.