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

基本信息

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
项目类别：
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

项目摘要

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.

描述：基因和寡核苷酸疗法有可能彻底改变许多疾病的治疗。但是，这些新药的安全是一个主要问题。特别关注的是，许多基于基因的药物会触发先天免疫系统的激活。这导致高度炎性细胞因子（例如I型干扰素和IL-6）的释放，这可能对受体有毒，甚至致命。先天反应还引发了一种适应性免疫反应，从而导致针对治疗转化产物的抗体产生产生，以及可以杀死细胞的细胞毒性T细胞表达替代基因，并消除治疗的益处。即使对基于基因的药物的化合物特异性修饰有时可以防止先天反应，但要提高基因和寡核苷酸疗法的安全性和效率，需要采取更一般的方法。我们的长期目标是开发一种防止对基因基因药物的炎症反应的方法，并使用基因转移来诱导抗原特异性耐受性，以防止不必要的免疫调查。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）利用这种作用来诱导免疫学耐受性。在最近的研究中，我们发现miR-126-VEGFR2轴是对核酸的先天反应所需的必要途径（Agudo等人自然免疫学2014）。根据我们的发现，我们假设MiR-126-VEGF信号通路控制了浆细胞样树突状细胞（PDC）子集的体内平衡和功能，这些细胞（PDC）负责识别和引发对治疗性DNA和RNA的炎症反应，并使用这种临床上的遗传供应，并且可以通过临床上的伴奏，可以阻止临床上的基因，并且可以使临床上的生物学生存下来，并且可以使临床上的生产力定期供应。药物，包括慢病毒载体和简短干扰RNA（siRNA）。为了检验我们的假设，我们将：（1）确定小鼠和人miR-126在对治疗载体和寡核苷酸的先天反应中的功能，（2）确定调节小鼠和人VEGFR2信号传导对炎症对治疗的影响的影响。核酸和（3）评估我们已经鉴定出未被核酸激活的新的PDC子集的靶标是否可以促进抗原特异性免疫耐受性。我们的研究结果将：发现对先天免疫学的新见解，尤其是与核酸与DC之间的相互作用相关的，提供了一种适用于临床适用的手段，以防止对某些基因和基于基于基因的基因的疗法的炎症反应，并建立一种诱导对抗原的耐受性的策略，从而构成抗原的抗原，以防止自动启用疫苗的基础，以防止自动降低自动性，从而构成抗原的基础。血友病。