Pachyonychia congenita clinical trial using therapeutic siRNAs

描述（由申请人提供）：摘要RNA干扰（RNAi）具有彻底改变显性遗传疾病治疗的潜力。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。使用siRNA的临床试验目前正在进行中，用于许多适应症，包括年龄相关性黄斑变性和呼吸道合胞病毒感染。迄今为止，尚未将皮肤病的siRNA治疗引入临床。在这项提案中，我们的目标是启用并启动先天性厚甲症（PC）的临床试验，这是一种由编码角蛋白6，16和17的基因突变（包括单核苷酸变化）引起的超罕见皮肤病。PC患者的主要抱怨是发生在足部压力点上或附近的使人衰弱的疼痛性老茧和起泡。正是脚底上的这些限定区域被靶向用于局部siRNA治疗。在该提案的第1阶段，我们扩展了先前的研究，研究了拟议的前导siRNA治疗剂的效力、持续时间和选择性，并在家兔中进行了FDA IND启用毒理学研究。最近在小鼠中完成了一项为期28天的毒性研究，预期在较高剂量下会发生局部毒性。拟定的家兔研究符合FDA的第二种属毒理学要求。在该提案的第2阶段，所有符合条件且愿意接受K6a N171K突变的美国患者将在1b期临床试验中接受治疗。我们希望这项试验是皮肤siRNA治疗的“首次人体试验”。虽然先天性甲肥厚是一种罕见的疾病，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、确定的区域中表达的确定的突变），并且所吸取的教训应易于推广到其他皮肤疾病。尽管发现了许多遗传性皮肤病的潜在突变，但很少有有效的治疗方法出现。siRNA可以被开发用于靶向特定疾病相关突变的发现预示着一种新的治疗模式的到来。我们已经确定了一种有效的和选择性的siRNA，其靶向角蛋白6a基因中的单核苷酸突变，该突变导致罕见的先天性厚甲皮肤病并阻断其表达。这种siRNA（FDA称为TD101）已被授予孤儿药地位，并处于IND启用测试的最后阶段（包括第1阶段提出的毒理学安全性测试），然后启动1b期临床试验（本提案的第2阶段）。在应用siRNA技术治疗PC中获得的经验教训应该容易推广到许多其他主要皮肤疾病，并可能推广到由突变或过度表达的致病基因引起的其他疾病。

DESCRIPTION (provided by applicant): ABSTRACT 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 number of indications including age- related macular degeneration and respiratory syncitial virus infection. No siRNA treatment of skin disorders has been introduced to date into the clinic. In this proposal we aim to enable and initiate a clinical trial of pachyonychia congenita (PC), an ultra-rare skin disorder resulting from mutations, including single nucleotide changes, in genes encoding keratins 6, 16, and 17. 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 that are targeted for local siRNA treatment. In Phase 1 of this proposal, we extend previous studies investigating the potency, duration and selectivity of the proposed lead siRNA therapeutic as well as perform an FDA IND-enabling toxicology study in rabbits. A 28-day tox study was recently completed in mice, with expected localized toxicity occurring at the higher doses. The proposed rabbit study fulfills the second species toxicology requirement of the FDA. In Phase 2 of this proposal, all eligible and willing U.S. patients containing the K6a N171K mutation will be treated in a Phase 1b clinical trial. We expect this trial to be 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. PUBLIC HEALTH RELEVANCE Despite the discovery of the underlying mutations responsible for many inherited skin diseases, few effective treatments have emerged. The discovery that siRNAs can be developed to target specific disease- related mutations portends the advent of a new treatment paradigm. We have identified a potent and selective siRNA that targets a single nucleotide mutation in the keratin 6a gene that is responsible for the rare skin disorder pachyonychia congenita and blocks its expression. This siRNA (known to the FDA as TD101) has been granted orphan drug status and is in the final stage of IND-enabling testing (including toxicology safety testing proposed in Phase 1) prior to initiating a Phase 1b clinical trial (Phase 2 of this proposal). The lessons learned in applying siRNA technology for treatment of PC should be readily generalizable to a host of other dominant skin disorders and likely to other disorders resulting from mutated or overexpressed disease- causing genes.