Versatile carriers for cell-specific siRNA delivery in vivo

用于细胞特异性 siRNA 体内递送的多功能载体

• 批准号: 8048377
• 负责人: Priti Kumar
• 金额: $ 23.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048377
• 关键词: Affinity; Antibodies; Binding; Biological; Blood; Blood Cells; Cell Line; Cell Surface Receptors; Cells; Clinical Trials; Coupled; Development; Disease; Drug Formulations; Evaluation; Fc Immunoglobulins; Gene Expression; Gene Silencing; Goals; Human; IL2RA gene; Immune; Immunoglobulins; Inflammation; Knockout Mice; Laboratories; Lead; Mediating; Modeling; Mononuclear; Mus; Nucleic Acids; Organ; Peptides; Preclinical Testing; Proteins; RNA; RNA Interference; Reagent; Research; Route; Screening procedure; Small Interfering RNA; Solid Neoplasm; Specificity; Surface Antigens; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Treatment Efficacy; base; cell type; cost; cost effective; design; human disease; in vivo; inhibitor/antagonist; innovation; interest; intravenous injection; mouse model; neoplastic cell; novel; preclinical evaluation; targeted delivery; uptake; user-friendly

DESCRIPTION (provided by applicant): The main obstacle to RNA-interference-based inhibitors is delivering them into primary cells that are highly recalcitrant to nucleic acid uptake. As a result suppression of target gene expression within these cells for both biological and therapeutic purposes has been a major issue. In recent years there have been several advances in siRNA-carrier design that have enabled efficient and cell-specific siRNA delivery. However, formulation of these carriers is extremely cumbersome and cost-prohibitive for preliminary laboratory testing. We propose to develop novel, cost-effective, easy-to-formulate and non-immunogenic siRNA carriers for the cell-specific delivery of siRNA in vivo. These carriers will be formulated from two components- (1) a non-immunogenic protein/peptide component that binds the immunoglobulin Fc-region with a high affinity coupled to a siRNA binding domain and (ii) an antibody component capable of recognizing a specific cell-surface receptor and inducing internalization. Simple mixing or incubation of the carrier with the antibody will yield a reagent capable of siRNA delivery to the desired cell type. Importantly, delivery to the target cell type/organ will be achieved through simple intravenous injections. We will generate siRNA carriers to each of the human immune cell subtypes and defined organs/tissues and evaluate siRNA treatment efficacy in relevant murine models of human disease. The successful completion of our research plan is expected to lead to the establishment of easily translatable delivery platforms for the preclinical evaluation of potential siRNA therapeutic candidates. PUBLIC HEALTH RELEVANCE: siRNAs represent the most promising of RNA-based therapeutics advancing into clinical trials but efficient delivery is still an issue. The availability of 'user-friendly' siRNA carriers for delivery into practically any cell type of choice would tremendously expand the applicability of the RNAi technology. Here we propose to develop easy-to-formulate non-immunogenic reagents for the delivery of siRNA specifically into multiple human cells thereby increasing the range of siRNA- amenable cell types for in vivo applications to counter disease states.

描述（由申请人提供）：基于RNA干扰的抑制剂的主要障碍是将它们递送到对核酸摄取高度抗拒的原代细胞中。因此，出于生物学和治疗目的抑制这些细胞内的靶基因表达一直是一个主要问题。近年来，siRNA 载体设计取得了一些进展，实现了高效且细胞特异性的 siRNA 递送。然而，这些载体的配制对于初步实验室测试来说极其麻烦且成本高昂。我们建议开发新颖、经济高效、易于配制且非免疫原性的 siRNA 载体，用于体内细胞特异性递送 siRNA。这些载体将由两种成分配制而成 - (1) 非免疫原性蛋白质/肽成分，以高亲和力结合免疫球蛋白 Fc 区，并与 siRNA 结合结构域偶联；(ii) 能够识别特定细胞的抗体成分-表面受体并诱导内化。载体与抗体的简单混合或孵育将产生能够将siRNA递送至所需细胞类型的试剂。重要的是，将通过简单的静脉注射实现向靶细胞类型/器官的递送。我们将为每种人类免疫细胞亚型和确定的器官/组织生成 siRNA 载体，并评估 siRNA 在人类疾病相关小鼠模型中的治疗效果。我们的研究计划的成功完成预计将导致建立易于翻译的递送平台，用于潜在 siRNA 治疗候选药物的临床前评估。 公共卫生相关性：siRNA 是最有前途的基于 RNA 的疗法，已进入临床试验，但有效的递送仍然是一个问题。能够将“用户友好”的 siRNA 载体递送到几乎任何选择的细胞类型中，将极大地扩展 RNAi 技术的适用性。在这里，我们建议开发易于配制的非免疫原性试剂，用于将 siRNA 特异性递送到多个人类细胞中，从而增加 siRNA 适合的细胞类型的范围，用于体内应用以对抗疾病状态。