Targeted genetic engineering of B cells to induce protective antibody responses to viral pathogens

B 细胞的靶向基因工程诱导针对病毒病原体的保护性抗体反应

基本信息

批准号：
10367785
负责人：
Jennifer Eileen Adair
金额：
$ 86.32万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-05 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367785
关键词：
Aftercare Antibodies Antibody Formation Antibody Response Antibody titer measurement Antigens B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Blood Cells COVID-19 pandemic Cells Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Country Coupled Development Engineering Ensure Formulation Gene Delivery Genes Genetic Genetic Engineering HIV Health Hematopoietic stem cells Hospitalization Human Immune Immune response Immunity Immunology Individual Infection Influenza Injections Laboratories Leukocytes Life Maintenance Mediating Memory Memory B-Lymphocyte Monoclonal Antibodies Mus Nature Pathogenicity Patients Plasma Plasma Cells Process Production Property Provider Publications Research Resources Respiratory Syncytial Virus Infections Respiratory Tract Infections Respiratory syncytial virus Role Science Serum Single-Stranded DNA Societies Source System Technology Testing Time Tissues Toxic effect United States Vaccination Vaccines Viral Viral Respiratory Tract Infection Virus Virus Diseases Visit Work World Health Organization adaptive immunity cell type cellular engineering cost effective cytotoxicity engineered stem cells gene therapy genetically modified cells genomic locus in vivo in vivo evaluation influenza virus strain mortality mouse model nanoGold nanoformulation nanoparticle neutralizing antibody novel novel strategies pathogenic virus peripheral blood prevent promoter rational design respiratory respiratory virus response safety and feasibility selective expression success synergism targeted delivery therapeutic genome editing tool vaccine strategy

Aftercare Antibodies Antibody Formation Antibody Response Antibody titer measurement Antigens B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Blood Cells COVID-19 pandemic Cells Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Country Coupled Development Engineering Ensure Formulation Gene Delivery Genes Genetic Genetic Engineering HIV Health Hematopoietic stem cells Hospitalization Human Immune Immune response Immunity Immunology Individual Infection Influenza Injections Laboratories Leukocytes Life Maintenance Mediating Memory Memory B-Lymphocyte Monoclonal Antibodies Mus Nature Pathogenicity Patients Plasma Plasma Cells Process Production Property Provider Publications Research Resources Respiratory Syncytial Virus Infections Respiratory Tract Infections Respiratory syncytial virus Role Science Serum Single-Stranded DNA Societies Source System Technology Testing Time Tissues Toxic effect United States Vaccination Vaccines Viral Viral Respiratory Tract Infection Virus Virus Diseases Visit Work World Health Organization adaptive immunity cell type cellular engineering cost effective cytotoxicity engineered stem cells gene therapy genetically modified cells genomic locus in vivo in vivo evaluation influenza virus strain mortality mouse model nanoGold nanoformulation nanoparticle neutralizing antibody novel novel strategies pathogenic virus peripheral blood prevent promoter rational design respiratory respiratory virus response safety and feasibility selective expression success synergism targeted delivery therapeutic genome editing tool vaccine strategy

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项目摘要

PROJECT SUMMARY / ABSTRACT In the United States alone, respiratory viral pathogenic infections such as influenza cause millions of provider visits and tens of thousands of work days lost, hundreds of thousands of hospitalizations and deaths. According to the World Health Organization, the number of viral pathogenic infections continues to rise with higher mortalities in resource limited countries. While a successful vaccine strategy is highly desirable, this approach relies on the induction of B cells to produce protective antibodies that either prevent viruses from entering cells or target infected cells for destruction. Unfortunately, successful vaccines for many viruses are not yet available after decades of research such a respiratory syncytial virus (RSV). In this proposal, we leverage a novel approach developed by Dr. Justin Taylor’s laboratory to genetically engineer B cells to express antibodies protective against respiratory viruses including RSV and influenza. This strategy has already been shown to result in the production of protective antibodies against influenza, RSV, and human immunodeficiency virus infection [Moffett et al., Science Immunology, 2019]. While this approach can ensure protective antibody production, the genetic engineering process required 10 days of complicated ex vivo manufacturing and is not broadly distributable. To overcome these barriers, we will co-opt a novel, synthetic nanoparticle that was developed in Dr. Jennifer Adair’s laboratory to deliver genetic engineering in a single, passive step [Shahbazi et al., Nature Materials, 2019]. We show that this nanoparticle can be assembled to genetically engineer primary human blood cells in less than 2 days, and can be modified to specifically interact with target blood cell types in vivo. Here we will develop this scalable nanoformulation as a vaccine-like in vivo delivery system to direct immune responses against respiratory viruses such as RSV. We will use these nanoparticles to directly genetically engineer the most protective primary B cell subtypes, and hematopoietic stem and progenitor cells, which can provide lifelong replenishment of protective B cells and antibodies. This research will not only develop a unique tool set against viral pathogens, but will provide transformative advances in equitable distribution of gene editing therapies.

项目摘要 /摘要仅在美国，呼吸道病毒致病性感染（例如影响力）会导致数百万提供者的访问和数以万计的工作日损失了，成千上万的住院和死亡人数。根据世界卫生组织的数据，病毒致病感染的数量继续在资源有限的国家中随着较高的死亡而上升。虽然成功的疫苗策略很高理想的是，这种方法依赖于B细胞的诱导来产生受保护的抗体防止病毒进入细胞或靶向感染细胞以破坏。不幸的是，成功经过数十年的研究，许多病毒的疫苗尚未获得这样的呼吸综合性病毒（RSV）。在此提案中，我们利用贾斯汀·泰勒博士的实验室开发的一种新颖方法向基因工程师B细胞表达抗体免受呼吸道病毒的抗体 RSV和Intallencena。该策略已被证明可以产生保护抗影响，RSV和人类免疫缺陷病毒感染的抗体[Moffett等人，科学免疫学，2019年]。尽管这种方法可以确保保护性抗体的产生，但遗传工程过程需要10天复杂的离体制造业，并且并不广泛可分发。为了克服这些障碍，我们将选择一种新颖的合成纳米颗粒在詹妮弗·阿黛尔（Jennifer Adair）博士的实验室中开发，以单一的，被动的步骤提供基因工程 [Shahbazi等人，自然材料，2019年]。我们证明该纳米颗粒可以组装到在不到2天的时间内，基因工程师的原代人血细胞，可以经过修改为在体内与靶血细胞类型相互作用。在这里，我们将开发这种可扩展的纳米制剂作为类似疫苗的体内输送系统，以直接针对呼吸道病毒的免疫反应，例如 RSV。我们将使用这些纳米颗粒直接加入最受保护的原代B细胞亚型以及造血茎和祖细胞，可以提供终身复制品保护性B细胞和抗体。这项研究不仅将开发针对病毒的独特工具病原体，但将提供基因编辑疗法公平分布的变革性进步。