Pachyonychia congenita clinical trial using therapeutic siRNAs

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）具有很强的效力和选择性，表现出显著的单核苷酸特异性。使用sirna的临床试验目前正在进行，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，还没有siRNA治疗皮肤病的方法被引入临床。在本提案中，我们的目标是启动并启动先天性厚甲癣（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患者的主要抱怨是使人衰弱的疼痛的老茧和水泡发生在或靠近脚部的压力点。正是这些脚底上的特定区域是局部siRNA治疗的目标。在该提案的第一阶段，我们扩展了先前的研究，调查了所提议的先导siRNA治疗的效力，持续时间和选择性，并在兔子中进行了FDA ind的毒理学研究。最近在老鼠身上完成了一项为期28天的毒性研究，预计高剂量会发生局部毒性。拟议的兔子研究满足FDA的第二个物种毒理学要求。在该提案的2期中，所有符合条件且愿意携带K6a N171K突变的美国患者将在1b期临床试验中接受治疗。我们期望这项试验成为siRNA在皮肤上治疗的“首次人体试验”。虽然先天性肿甲是一种罕见的疾病，但该疾病的性质使其成为初始siRNA临床试验的理想原型皮肤病（定义突变，在有限的，确定的区域表达），并且吸取的经验教训应该很容易推广到其他皮肤病。尽管发现了导致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可以被开发来靶向特定疾病相关的突变，这一发现预示着一种新的治疗模式的出现。我们已经确定了一种有效的选择性siRNA，其靶向角蛋白6a基因中的单个核苷酸突变，该基因负责罕见的皮肤疾病先天性厚甲癣并阻断其表达。该siRNA （FDA称为TD101）已被授予孤儿药地位，并处于启动1b期临床试验（该提案的2期）之前的ind启用测试的最后阶段（包括1期建议的毒理学安全性测试）。应用siRNA技术治疗PC的经验教训应该很容易推广到许多其他显性皮肤病，以及可能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.