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: 8530953
• 负责人: ROGER L KASPAR
• 金额: $ 104.58万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530953
• 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 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.

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。

项目成果

Non-Invasive Intravital Imaging of siRNA-Mediated Mutant Keratin Gene Repression in Skin.

siRNA 介导的皮肤突变角蛋白基因抑制的非侵入性活体成像。

• DOI: 10.1007/s11307-015-0875-z
• 发表时间: 2016
• 期刊: Molecular imaging and biology
• 影响因子: 3.1
• 作者: Hickerson,RobynP;Speaker,TychoJ;Lara,MariaFernanda;González-González,Emilio;Flores,ManuelA;Contag,ChristopherH;Kaspar,RogerL
• 通讯作者: Kaspar,RogerL

Gene silencing following siRNA delivery to skin via coated steel microneedles: In vitro and in vivo proof-of-concept.

• DOI: 10.1016/j.jconrel.2012.12.030
• 发表时间: 2013-03-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Chong RH;Gonzalez-Gonzalez E;Lara MF;Speaker TJ;Contag CH;Kaspar RL;Coulman SA;Hargest R;Birchall JC
• 通讯作者: Birchall JC