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）有可能彻底改变显性遗传疾病的治疗。小抑制RNA（siRNA）是高度有效和选择性的，表现出显着的单核苷酸特异性。目前正在进行使用siRNA的临床试验，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siRNA治疗皮肤病的方法。 到目前为止，已进入临床。该提案是用于使用TD 101进行先天性厚甲症（PC）的临床试验，这是一种非常罕见的遗传性皮肤病。TD101是一种siRNA，其特异性且有效地靶向编码角蛋白6a（K6a）的基因中的单核苷酸突变，导致天冬酰胺至赖氨酸的致病性氨基酸改变。PC患者的主要抱怨是使人虚弱，痛苦的老茧， 在足部压力点上或附近发生的起泡。正是K6a N171K突变携带者脚底上的这些限定区域在拟议的临床试验中被靶向用于局部siRNA治疗。所有已知的、符合条件的和有意愿的K6a N171K突变的美国患者将在1b期临床试验中接受治疗。该试验是皮肤中siRNA治疗的“首次人体试验”。 虽然先天性甲肥厚是一种罕见疾病，但这种疾病的性质使其成为初始siRNA临床试验的理想原型皮肤疾病（在有限的、限定的区域中表达的限定突变），并且所吸取的经验教训应易于推广到其他皮肤疾病，包括罕见疾病，如单纯性大疱性表皮病。

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.