Pachyonychia congenita clinical trial using therapeutic siRNAs

使用治疗性 siRNA 进行先天性厚甲症临床试验

• 批准号: 7539266
• 负责人: ROGER L KASPAR
• 金额: $ 31.27万
• 依托单位: TRANSDERM, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539266
• 关键词: Age related macular degeneration; Area; Bulla; Clinic; Clinical Treatment; Clinical Trials; Disease; Dose; Double-Blind Method; Effectiveness; Genes; Goals; Grant; Hereditary Disease; Inherited; Keratin; Lead; Learning; Localized; Molecular; Mus; Mutate; Mutation; Nature; Nucleotides; Numbers; Orphan Drugs; Oryctolagus cuniculus; Pain; Patients; Phase; Phase II Clinical Trials; Placebos; Protein Overexpression; Public Health; RNA Interference; Rare Diseases; Registries; Research; Reverse Transcriptase Polymerase Chain Reaction; Safety; Skin; Small Interfering RNA; Specificity; Staging; Technology; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Toxicology; United States Food and Drug Administration; Virus Diseases; Week; abstracting; base; day; expectation; foot; foot sole; keratinocyte; mutant; novel therapeutics; patient advocacy group; pressure; prototype; respiratory; skin disorder

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.

描述（由申请人提供）：摘要RNA干扰（RNAi）具有革新主要遗传疾病治疗的潜力。小型抑制性RNA（siRNA）具有很高的有效性和选择性，表现出显着的单核苷酸特异性。目前，使用siRNA的临床试验正在进行许多指示，包括与年龄相关的黄斑变性和呼吸临床病毒感染。迄今为止，尚未引入siRNA对皮肤疾病的治疗。在这一提议中，我们旨在启动和启动Pachyonychia argenita（PC）的临床试验，这是一种超稀有的皮肤疾病，这是一种突变引起的突变，包括单核苷酸的变化，编码角蛋白6、16和17的基因。PC患者的主要抱怨是衰弱的conteration和blisteration the PC患者的严重痛苦和水泡，这是在或接近水平的，这是脚下或接近压力点的脚步。正是这些针对局部siRNA处理的脚底上的定义区域。在该提案的第1阶段中，我们扩展了先前的研究，研究了所提出的铅siRNA治疗性的效力，持续时间和选择性，并在兔子中进行FDA辅助毒理学研究。最近在小鼠中完成了28天的TOX研究，预计局部毒性发生在更高剂量的情况下。拟议的兔子研究满足了FDA的第二种物种毒理学要求。在该提案的第2阶段，将在1B期临床试验中治疗所有合格且愿意的美国患者。我们预计该试验将成为皮肤中siRNA治疗的“人类第一名”。尽管Pachyonychia congenita是一种罕见的疾病，但该疾病的性质使其成为最初的siRNA临床试验的理想原型皮肤疾病（在有限的，定义的区域中表达的突变），并且应容易将所学的经验教训概括为其他皮肤疾病。尽管发现了导致许多遗传性皮肤疾病的基础突变，但公共卫生的相关性很少。可以开发siRNA来瞄准特定疾病相关的突变的发现预示着新的治疗范式的出现。我们已经确定了一种有效和选择性的siRNA，该siRNA靶向角蛋白6a基因中的单个核苷酸突变，该突变负责稀有皮肤疾病Pachyonychia congenita并阻止其表达。该siRNA（FDA称为TD101）已被授予孤儿药物状态，并处于启动1B期临床试验（本提案的第2阶段）之前，处于辅助测试的最后阶段（包括在第1阶段提出的毒理学安全测试）。应用siRNA技术治疗PC的经验教训应容易被推广到许多其他主要的皮肤疾病，可能是由于突变或过表达的疾病引起的基因而导致的其他疾病。