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In vivo CRISPR engineering of B cells to produce anti-HIV broadly neutralizing antibodies using novel nanoparticles

B 细胞体内 CRISPR 工程利用新型纳米粒子产生抗 HIV 广泛中和抗体

基本信息

批准号：
10374397
负责人：
Jennifer Eileen Adair
金额：
$ 87.79万
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：
2022-06-08 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374397
关键词：
Anti-Retroviral Agents Antibodies Antibody Formation Antibody Therapy Antigens Autologous Transplantation B-Lymphocytes Bar Codes Blood Cells Bone Marrow CRISPR/Cas technology Cell Survival Cell surface Cells Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Coupling DNA Data Engineering Ensure Epidemic Frequencies Gene Delivery Genes Genetic Genetic Engineering HIV HIV Infections Half-Life Hematopoietic stem cells Human Human Herpesvirus 4 Humoral Immunities Immune Immunity Immunoglobulin G Immunoglobulin-Secreting Cells Immunology Injections Interruption Intervention Laboratories Life Liver Mediating Memory B-Lymphocyte Modeling Molecular Target Mus Nature Patients Persons Pharmaceutical Preparations Plasma Cells Process Proliferating Research Resources Respiratory syncytial virus Risk Science Single-Stranded DNA Source Surface System Technology Testing Therapeutic Time Tissues Transplantation Vaccines Viral Viral Vector Virus Diseases Work antibody engineering cell type clinically relevant cost cost effective design experience fitness gene therapy genetically modified cells immunogenic improved in vivo in vivo evaluation influenzavirus lipid nanoparticle mouse model nanoGold nanoformulation nanoparticle neutralizing antibody nonhuman primate novel novel strategies preference prevent promoter side effect simian human immunodeficiency virus success synergism therapeutic genome editing tool viral rebound

项目摘要

PROJECT SUMMARY / ABSTRACT The quest for an HIV cure remains incomplete, nearly half a century since the onset of the epidemic. Antiretroviral drug cocktails can suppress HIV infection, but suffer in their success owing to side effects and limitations in access and compliance. Injection of broadly neutralizing antibodies (bNAbs) to prevent HIV rebound has had some success, but requires regular re-injection of multiple antibodies to maintain suppression and viral escape. Thus, cost and continued access remain limitations. Genetic engineering of patient cells has been proposed to overcome all of these shortfalls, and could constitute a one-time treatment with lifelong therapeutic value if successful. In this proposal, we leverage a novel approach developed by Dr. Justin Taylor’s laboratory to genetically engineer B cells to express bNAbs for the treatment of human immunodeficiency virus (HIV). This strategy has already been used to engineer B cells to produce antibodies protective against influenza virus, respiratory syncytial virus, Epstein-barr virus and HIV [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 in less than a day to genetically engineer unstimulated, primary human blood cells 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 humoral immunity with multiple bNAbs in a clinically-relevant nonhuman primate model of HIV infection. We will use these nanoparticles to directly genetically engineer native primary B cell subtypes, and hematopoietic stem and progenitor cells, which can provide lifelong replenishment of antibody- producing B cells. This research will not only develop a unique tool set against HIV but will provide transformative advances in equitable distribution of gene editing therapies.

项目摘要/摘要