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In Vivo Gene Editing of B cells with NICE-AAV Vectors

使用 NICE-AAV 载体对 B 细胞进行体内基因编辑

基本信息

批准号：
10541906
负责人：
Christopher W Peterson
金额：
$ 77.18万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-16 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10541906
关键词：
2019-nCoV Address Anatomy Animals Antibodies Antibody Therapy Antigens Autoimmune Diseases B-Lymphocytes Biological Assay CRISPR/Cas technology Capsid Cells Clinical Clinical Research Communicable Diseases Data Dependovirus Disease remission Dose Engineering Experimental Designs Failure Gene Transduction Agent Genes Genetic Goals HIV HIV Antibodies HIV-1 HIV/AIDS Human IGH@ gene cluster Immune response Immune system Immunocompetent Immunodeficient Mouse Immunoglobulin G Individual Infection Injections Knock-in Libraries Link Lymphocyte Macaca mulatta Malignant Neoplasms Measures Methodology Methods Modality Modeling Monoclonal Antibodies Monoclonal Antibody Therapy Mus Nature Pathology Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phenotype Proteins Publications Publishing Regimen Resource-limited setting Secondary to Serum Site Specificity Technology Testing Therapeutic Therapeutic Effect Therapeutic antibodies Time Tissues Transgenes Tropism Variant Viral Viral Antigens Viremia Virus Virus Replication Withdrawal adeno-associated viral vector antiretroviral therapy chimeric antigen receptor T cells clinical application delivery vehicle experimental study fighting gene therapy genetic information global health humanized mouse immunogenic immunogenicity in vivo innovation neutralizing antibody nonhuman primate novel preclinical study programs screening simian human immunodeficiency virus success tool trafficking transduction efficiency vector vector biodistribution viral rebound

项目摘要

ABSTRACT HIV-specific gene therapies are a powerful and promising means to achieve HIV cure/stable remission in the absence of antiretroviral therapy (ART). Broadly neutralizing antibodies (bNAbs) and analogous molecules such as eCD4-Ig offer one of the clearest paths to a cure, but are hindered by three key obstacles. First, passive administration of bNAb/eCD4-Ig proteins is by definition a transient therapy; when circulating levels of these potent anti-HIV factors decline, virus replication is able to resume. Second, gene therapy vector-based approaches including adeno-associated virus (AAV) support prolonged expression of bNAbs and other antiviral transgenes, but are frequently limited by host immune responses. Third, potent ART regimens suppress viral replication to extremely low levels, rendering engineered HIV-specific lymphocytes unable to recognize and clear persistently infected cells. We have generated an exciting set of tools and preliminary data that directly addresses each of these barriers. To overcome the transient nature of bNAbs and associated immunogenicity of vectored delivery approaches, we have performed an in vivo screen in nonhuman primates (NHP) and identified engineered AAV variants that persist long term (consistent with a lack of recognition by the host immune system), and specifically target B cells. B cell tropic vectors will be packaged with CRISPR-Cas9 gene editing machinery, applying highly innovative covalent linkage methodology to double our vectors’ packaging capacity. We refer to our novel in vivo delivery approach as Non-Immunogenic, Cargo-Enhanced (NICE) AAV: in a single dose, NICE- AAV vectors will specifically reprogram B cells with bNAb or eCD4-Ig sequences targeted to the native IgG locus. Finally, we will overcome the significant problem of insufficient viral antigen by supplying cell-associated HIV-1 Env in trans. Our recent publication in the NHP model demonstrates the immense success of this strategy to stimulate HIV-1-specific chimeric antigen receptor (CAR) T cells and should similarly boost and trigger expansion of our gene-edited B cells. The central goals of our proposal are to validate the efficiency and specificity of B cell-targeted NICE-AAV (AIM 1), to demonstrate that this in vivo delivery approach enables persistent bNAb/eCD4-Ig expression in HIV anatomical compartments and reservoir sites (AIM 2), and most importantly, to achieve a therapeutic impact in humanized mouse and NHP models of HIV persistence (AIM 3). We will merge one of the most promising therapeutic modalities for HIV cure (bNAbs/eCD4-Ig) with our extremely unique in vivo delivery platform (NICE-AAV). Importantly, this approach will be applicable not only for HIV-1, but for the broad range of pathologies where monoclonal antibody therapies offer clinical benefit.

摘要