Pachyonychia congenita clinical trial using therapeutic self-delivery siRNAs

使用治疗性自我递送 siRNA 进行先天性厚甲症临床试验

• 批准号: 8203881
• 负责人: ROGER L KASPAR
• 金额: $ 208.8万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203881
• 关键词: Analgesics; Area; Biological Assay; Bulla; Clinical; Clinical Trials; Disease; Drug Formulations; Epidermis; Funding; Genes; Hereditary Disease; Human; Immunocompromised Host; Inherited; Injection of therapeutic agent; Intralesional Injections; Keratin; Learning; Lesion; Modeling; Mus; Mutate; Mutation; Nature; Nerve Block; Nucleotides; Oryctolagus cuniculus; Pain; Patients; Peripheral Blood Mononuclear Cell; Phase; Quality Control; RNA Interference; Rare Diseases; Route; Safety; Skin; Skin Transplantation; Skin graft; Small Interfering RNA; Specificity; System; Technology; Testing; Therapeutic; Therapeutic Uses; Time; Toxicology; Whole Blood; design; effective therapy; foot; foot sole; intradermal injection; keratinocyte; man; mutant; oral pain; overexpression; preclinical study; pressure; prevent; prototype; skin disorder; stability testing

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 number of indications including skin. Facilitated by Phase 1 funding, a small one patient phase 1b clinical trial was undertaken for pachyonychia congenita (PC). This ultrarare skin disorder is caused by mutations, including single nucleotide changes, in the 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. These defined regions on the soles of the feet were targeted for local siRNA treatment by intralesional injection of siRNA (TD101) with encouraging results. Unfortunately, the pain associated with injections into lesions (oral pain medication and regional nerve blocks were required to allow treatment), prevents widespread use of this mode of administration. This observation has led to intense efforts to identify patient-friendly (i.e., little or no pain) delivery options. This clinical trial was the first human use of siRNA in skin and also the first siRNA to target a mutated gene. In Phase 2 of this proposal, we extend the progress of Phase 1 and the Phase 1b clinical trial. We have found that unmodified or stabilized siRNAs are not taken up readily by skin keratinocytes but that modified, so-called "self-delivery" (sd) siRNAs are. Additional optimization of the sd-siRNA will be undertaken in mouse and human skin models followed by synthesis of GMP material for mouse and rabbit toxicology studies and clinical trials in which the siRNA will be delivered by dissolvable microneedle arrays or a topical GeneCream" formulation, both developed and manufactured at TransDerm. GeneCream and microneedle arrays are both designed to effectively deliver sd-siRNA with little or no pain (microneedle protrusions are designed to only penetrate to the non-innervated epidermis). Although PC 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 first-in-man siRNA skin clinical trials, and we fully expect the lessons learned will 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) was successfully tested in a Phase 1b clinical trial. Despite signs of efficacy, the painful nature of the administration route (intradermal injection of large volumes) required that we develop a more patient-friendly delivery system. Phase 2 of this proposal allows preclinical studies enabling a second clinical trial using microneedles loaded with a self-delivery version of TD101 siRNA. 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）：RNA干扰（RNAI）具有革命性治疗主要遗传疾病的潜力。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适应症，包括皮肤。在第1阶段资助的促进下，对Pachyonychia congenita（PC）进行了一项小型患者1B临床试验。这种超级男性皮肤疾病是由编码角蛋白6、16和17的基因中的突变引起的。PC患者的主要抱怨是在脚部压力点上或附近发生衰弱的疼痛的calling和泡沫。这些脚底上的定义区域是通过siRNA内注射（TD101）的局部siRNA治疗的，并令人鼓舞的结果。不幸的是，与注射病变相关的疼痛（需要口服止痛药物和区域神经阻滞以允许治疗），可防止这种给药方式广泛使用。这一观察结果导致了巨大的努力，以识别患者友好型（即几乎没有疼痛）的分娩选择。该临床试验是siRNA在皮肤中的首次使用，也是第一个靶向突变基因的siRNA。 在本提案的第2阶段，我们扩展了第1阶段和1B期临床试验的进展。我们发现，未修改或稳定的siRNA不容易被皮肤角质形成细胞吸收，而是经过修改的，所谓的“自我交付”（SD）sirnas。 Additional optimization of the sd-siRNA will be undertaken in mouse and human skin models followed by synthesis of GMP material for mouse and rabbit toxicology studies and clinical trials in which the siRNA will be delivered by dissolvable microneedle arrays or a topical GeneCream" formulation, both developed and manufactured at TransDerm. GeneCream and microneedle arrays are both designed to effectively deliver sd-siRNA with little or no pain （微针突起旨在仅穿透非发射表皮），尽管PC是一种罕见的疾病，但该疾病的性质使其成为理想的原型皮肤疾病（在有限的，有限的，定义的区域中定义的突变），用于首次人体sirna sirna sirna sirna临床试验，并且我们预计这些经验教训会成为其他皮肤疾病。 公共卫生相关性：尽管发现了导致许多遗传性皮肤疾病的潜在突变，但很少有有效的治疗方法。可以开发siRNA来瞄准特定疾病相关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）在1B期临床试验中已成功测试。尽管有疗效的迹象，但管理路线的痛苦性质（大量大量注射）要求我们发展一个更适合患者的送货系统。该提案的第2阶段允许临床前研究，可以使用带有TD101 siRNA的自传递版本的微针进行第二次临床试验。应用siRNA技术治疗PC的经验教训应很容易被推广到许多其他主要的皮肤疾病，并且可能是由于突变或过表达致病基因而导致的其他疾病。