Orally administered anti-TNFalpha RNAi therapeutic for autoimmune disorders

描述(申请人提供)：将小干扰RNA(SiRNAs)导入细胞，通过RNA干扰(RNAi)导致有效和特定的基因沉默。不幸的是，尽管基于siRNA的药物代表了一种潜在的重要治疗范例，但由于缺乏有效、无毒和组织特异性的递送系统，将这项技术应用于人类疾病，特别是与慢性炎症相关的疾病的能力受到阻碍。我们最近已经证明，P1，3-D-葡聚糖颗粒可以有效地通过口服给药将siRNA输送到巨噬细胞(Aouadi，Tesz等人)。2009年)。由于低剂量的口服化学合成的寡核苷酸以前被认为是不可能的，这一发现被视为一项重大的科学突破。这项建议的目的是利用这项技术开发一种以肿瘤坏死因子α为靶向siRNA的葡聚糖颗粒，并在公认的炎症模型中验证该平台的有效性。该项目的完成预计将使口服抗炎药的临床前/临床开发工作取得快速进展，用于治疗炎症性肠病、类风湿性关节炎和牛皮癣等自身免疫性疾病。 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。有效的输送是治疗发展的主要障碍。我们最近已经证明，1，3-D-葡聚糖颗粒可以通过口服有效地将siRNA输送到巨噬细胞(Aouadi，Tesz等人)。2009年)。该项目的完成预计将使口服抗炎药的临床前/临床开发工作取得快速进展，首先用于治疗自身免疫性疾病，如炎症性肠道疾病、类风湿性关节炎和牛皮癣。

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.