Phase Ib trial of TD101 siRNA for pachyonychia congenita (IND 77,504, 12-03-07)

描述(由申请人提供)： RNA干扰(RNAi)有可能使显性遗传疾病的治疗发生革命性变化。小分子抑制性RNA(SiRNAs)是一种高效、选择性强的单核苷酸特异性分子。使用siRNAs的临床试验目前正在进行中，用于一些适应症，包括年龄相关性黄斑变性和呼吸道合胞病毒感染。目前还没有针对皮肤病的siRNA治疗 到目前为止被引入诊所。这项提议是为了使用TD101进行一项针对先天性厚甲(PC)的临床试验，PC是一种极其罕见的遗传性皮肤病。TD101是一种针对编码角蛋白6a(K6a)基因的单核苷酸突变的siRNA，导致天冬酰胺转变为赖氨酸。PC患者的主要主诉是虚弱、疼痛的老茧和 发生在脚的压力点或其附近的水泡。在拟议的临床试验中，K6a N171K突变携带者脚底的这些指定区域将作为局部siRNA治疗的目标。所有已知的、符合条件的和愿意接受K6a N171K突变的美国患者将在1b期临床试验中接受治疗。这项试验是第一次在皮肤上进行siRNA治疗。 虽然先天性厚甲是一种罕见的疾病，但这种疾病的性质使其成为最初siRNA临床试验的理想皮肤病原型(已定义的突变，在有限的已定义区域表达)，所学到的经验应很容易推广到其他皮肤疾病，包括罕见的疾病，如单纯性大疱性表皮松解症。

DESCRIPTION (provided by applicant): RNA interference (RNAi) has the potential to revolutionize treatment of dominant genetic disorders. Small inhibitory RNAs (siRNAs) are highly potent and selective, demonstrating remarkable single-nucleotide specificity. Clinical trials using siRNAs are currently underway for a few indications including age-related macular degeneration and respiratory syncitial virus infection. No siRNA treatment of skin disorders has been introduced into the clinic to date. This proposal is for a clinical trial for pachyonychia congenita (PC), an ultra-rare genetic skin disorder, using TD101. TD101 is a siRNA that specifically and potently targets a single nucleotide mutation in the gene encoding keratin 6a (K6a), resulting in a pathogenic amino acid change of asparagine to lysine. The major complaint of PC patients is the debilitating, painful callusing and blistering which occurs on or near the pressure points of the feet. It is these defined regions on the soles of the feet of K6a N171K mutation carriers that are targeted for local siRNA treatment in the proposed clinical trial. All known, eligible and willing U.S. patients with the K6a N171K mutation will be treated in a Phase 1b clinical trial. This trial is the "first-in-man" for siRNA treatment in skin. Although pachyonychia congenita is a rare disease, the nature of the disorder makes it an ideal prototype skin disorder (defined mutations with expression in limited, defined areas) for an initial siRNA clinical trial and the lessons learned should be readily generalized to other skin disorders including rare disorders such as epidermolysis bullosa simplex.