Orally administered anti-TNFalpha RNAi therapeutic for autoimmune disorders

口服抗 TNFα RNAi 疗法治疗自身免疫性疾病

• 批准号: 8109927
• 负责人: ANASTASIA KHVOROVA
• 金额: $ 29.85万
• 依托单位: RXI PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109927
• 关键词: 3-Dimensional; Address; Air; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Atherosclerosis; Autoimmune Diseases; Biological Assay; Cells; Characteristics; Chemistry; Chronic; Chronic Cancer Pain; Clinical; Collaborations; Development; Diabetes Mellitus; Disease; Disease model; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Encapsulated; Foundations; Future; Gene Expression; Gene Silencing; Gene Targeting; Glucans; HIV; Health; Housekeeping Gene; Human; Immune; Immune system; In Vitro; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Intravenous; Kidney; Lead; Measures; Messenger RNA; Modeling; Nature; Oligonucleotides; Oral; Oral Administration; Pathway interactions; Penetration; Performance; Peritoneal Macrophages; Phagocytes; Pharmaceutical Preparations; Procedures; Protocols documentation; Psoriasis; Publications; Publishing; Quality Control; RNA; RNA Interference; Reagent; Research; Rheumatoid Arthritis; Small Interfering RNA; Stomach; System; Technology; Testing; Therapeutic; Tissues; Toxic effect; Validation; base; cytotoxicity; human disease; in vivo; macrophage; new technology; particle; pre-clinical; small molecule; therapeutic development; tool

DESCRIPTION (provided by applicant): Introduction of small interfering RNAs (siRNAs) into cells results in potent and specific gene silencing by RNA interference (RNAi). Unfortunately, while siRNA-based drugs represent a potentially significant therapeutic paradigm, the ability to apply this technology to human afflictions, in particular, diseases associated with chronic inflammation, has been impeded by the absence of efficient, non-toxic and tissue-specific delivery systems. We have recently shown that P1, 3-D-Glucan particles can be efficiently employed to deliver siRNAs to macrophages via oral administration (Aouadi, Tesz et al. 2009). As low dose, oral administration of chemically synthesized oligonucleotides was previously thought to be impossible, this discovery is viewed as a significant scientific breakthrough. The objective of this proposal is to employ this technology to develop a Glucan particle formulated with TNFalpha targeting siRNAs and validate this platform's efficacy in accepted models of inflammation. Completion of this project is expected to enable rapid progression into the preclinical /clinical development of an orally administered anti-inflammatory drug, for autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis and psoriasis. PUBLIC HEALTH RELEVANCE: RNAi (RNA interference) has large potential for the treatment of human disease. Efficient delivery is a major road block for therapeutic development. We have recently shown that 1, 3-D-Glucan particles can be efficiently employed to deliver siRNAs to macrophages via oral administration (Aouadi, Tesz et al. 2009). Completion of this project is expected to enable rapid progression into the preclinical /clinical development of an orally administered anti-inflammatory drug, first for autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis and psoriasis.

描述（由申请人提供）：将小干扰RNA（siRNA）引入细胞中，通过RNA干扰（RNAi）导致有效和特异性基因沉默。不幸的是，虽然基于siRNA的药物代表了潜在的重要治疗范例，但将该技术应用于人类痛苦，特别是与慢性炎症相关的疾病的能力受到缺乏有效、无毒和组织特异性递送系统的阻碍。我们最近表明，β 1，3-D-葡聚糖颗粒可有效用于通过口服给药将siRNA递送至巨噬细胞（Aouadi，Tesz等人，2009）。由于化学合成的寡核苷酸的低剂量口服给药以前被认为是不可能的，这一发现被视为一个重大的科学突破。该提案的目的是利用该技术开发用TNF α靶向siRNA配制的葡聚糖颗粒，并验证该平台在公认的炎症模型中的功效。该项目的完成预计将使口服抗炎药物的临床前/临床开发快速进展，用于自身免疫性疾病，如炎症性肠病，类风湿性关节炎和银屑病。 公共卫生相关性：RNAi（RNA干扰）在治疗人类疾病方面具有巨大的潜力。有效递送是治疗开发的主要障碍。我们最近已经表明，1，3-D-葡聚糖颗粒可以有效地用于通过口服给药将siRNA递送至巨噬细胞（Aouadi，Tesz等人，2009）。该项目的完成预计将使口服抗炎药的临床前/临床开发快速发展，首先用于自身免疫性疾病，如炎症性肠病，类风湿性关节炎和银屑病。