Modulating Immunity to Nucleic Acids and Inducing Tolerance by Gene Transfer

通过基因转移调节核酸免疫并诱导耐受

• 批准号: 8886697
• 负责人: Brian D Brown
• 金额: $ 42.1万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886697
• 关键词: Acute; Address; Adenovirus Vector; Agonist; Antibody Formation; Antigen Targeting; Antigens; Autoimmune Diseases; Autoimmunity; Biology; Blood Coagulation Factor; CD8B1 gene; Capsid; Cells; Cessation of life; Clinic; Cytotoxic T-Lymphocytes; DNA; Data; Dendritic Cells; Development; Diabetes Mellitus; Disease; Employee Strikes; Gene Delivery; Gene Expression Profile; Gene Transfer; Genes; Goals; Hemophilia A; Homeostasis; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunology; Impairment; Individual; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Insulin-Dependent Diabetes Mellitus; Interferon Type I; Interferons; Interleukin-6; Knock-out; Lentivirus Vector; Mediating; Medicine; MicroRNAs; Modification; Molecular; Mus; Natural Immunity; Nature; Nucleic Acids; Oligonucleotides; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Plasmids; Population; RNA; Receptor Signaling; Resistance; Risk; Role; Safety; Signal Pathway; Signal Transduction; T-Lymphocyte; TLR7 gene; Technology; Testing; Therapeutic; Toll-like receptors; Toxic effect; Transgenes; Vaccines; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Viral Vector; adaptive immunity; adeno-associated viral vector; base; cell killing; cytokine; drug efficacy; gene replacement; gene therapy; human TLR7 protein; improved; insight; islet; mouse model; novel; preclinical study; prevent; public health relevance; receptor; response; sensor; therapeutic DNA; therapeutic RNA; therapeutic transgene; vector

 DESCRIPTION: Gene and oligonucleotide therapies have the potential to revolutionize the treatment of many diseases. However, the safety of these new drugs is a major issue. Of particular concern, many gene-based medicines trigger activation of the innate immune system. This results in the release of highly inflammatory cytokines, such as type I interferons and IL-6, which can be toxic to the recipient, and even deadly. The innate response also initiates an adaptive immune response that results in production of antibodies against the therapeutic transgene product, as well as cytotoxic T cells that can kill cells expressing the replacement gene, and eliminate the benefits of the therapy. Even though compound-specific modifications to gene-based drugs can sometimes prevent the innate response, a more general approach is greatly needed to improve the safety and efficacy of gene and oligonucleotide therapy. Our long-term goal is to develop a means to prevent the inflammatory response to gene-based drugs, and to use gene transfer to induce antigen-specific tolerance for preventing unwanted immune responses. The objectives of this project are: (i) to identify molecular and cellular pathways that control the innate response to oligonucleotides and gene vectors, (ii) to target these pathways to dampen the innate response to gene delivery, and (ii) to exploit this effect for inducing immunological tolerance. In recent studies, we have discovered that the miR-126-VEGFR2 axis serves as an essential pathway required for the innate response to nucleic acids (Agudo et al. Nature Immunology 2014). Based on our findings, we hypothesize that the miR-126-VEGF signaling pathway controls the homeostasis and function of a subset of plasmacytoid dendritic cells (pDC) that are responsible for recognizing and initiating the inflammatory response to therapeutic DNA and RNA, and that blocking this pathway, using clinically approved drugs, can blunt both the innate and adaptive immune response to specific gene-based drugs, including lentiviral vectors and short interfering RNAs (siRNA). To test our hypotheses, we will: (1) Identify the function of mouse and human miR-126 in the innate response to therapeutic vectors and oligonucleotides, (2) determine the impact of modulating mouse and human VEGFR2 signaling on the inflammatory response to therapeutic nucleic acids, and (3) evaluate whether targeting antigen to a new pDC subset that we have identified which are not activated by nucleic acids, can promote antigen-specific immune tolerance. The results of our studies will: uncover new insights into innate immunity, particularly related to the interactions between nucleic acids and DCs, provide a clinically applicable means to prevent the inflammatory response to some gene and oligo-based therapies, and establish a strategy for inducing tolerance to an antigen, which will form the basis of a vaccine for reversing autoimmunity and for preventing the immune response to replacement coagulation factor in hemophiliacs.

 基因和寡核苷酸疗法有可能彻底改变许多疾病的治疗。然而，这些新药的安全性是一个主要问题。特别值得关注的是，许多基于基因的药物会激活先天免疫系统。这导致高度炎性细胞因子的释放，例如I型干扰素和IL-6，其对接受者可能是有毒的，甚至是致命的。先天性应答还启动适应性免疫应答，其导致产生针对治疗性转基因产物的抗体，以及细胞毒性T细胞，其可以杀死表达替代基因的细胞，并消除治疗的益处。尽管对基于基因的药物进行化合物特异性修饰有时可以防止先天性反应，但非常需要一种更通用的方法来提高基因和寡核苷酸治疗的安全性和有效性。 我们的长期目标是开发一种方法来防止对基于基因的药物的炎症反应，并使用基因转移来诱导抗原特异性耐受以防止不必要的免疫反应。该项目的目标是：（i）确定控制对寡核苷酸和基因载体的先天反应的分子和细胞途径，（ii）靶向这些途径以抑制对基因递送的先天反应，以及（ii）利用这种效应诱导免疫耐受。 在最近的研究中，我们发现miR-126-VEGFR 2轴是对核酸的先天性应答所需的重要途径（Agudo et al. Nature Immunology 2014）。基于我们的发现，我们假设miR-126-VEGF信号通路控制浆细胞样树突状细胞（pDC）亚群的稳态和功能，浆细胞样树突状细胞（pDC）负责识别和启动对治疗性DNA和RNA的炎症反应，并且使用临床批准的药物阻断该通路可以减弱对特定基因药物的先天性和适应性免疫反应，包括慢病毒载体和短干扰RNA（siRNA）。 为了验证我们的假设，我们将：（1）鉴定小鼠和人miR-126在对治疗性载体和寡核苷酸的先天应答中的功能，（2）确定调节小鼠和人VEGFR 2信号传导对对治疗性核酸的炎症应答的影响，和（3）评估是否将抗原靶向我们已经鉴定的不被核酸激活的新pDC亚群，可促进抗原特异性免疫耐受。我们的研究结果将：揭示了对先天免疫的新认识，特别是与核酸和DC之间的相互作用有关的认识，提供了一种临床上适用的方法来预防对某些基因和寡核苷酸治疗的炎症反应，并建立了诱导对抗原耐受的策略，其将形成用于逆转自身免疫和用于预防血友病患者对替代凝血因子的免疫应答的疫苗的基础。