Viral vector technology for cell type specific gene delivery

用于细胞类型特异性基因传递的病毒载体技术

基本信息

批准号：
10581499
负责人：
Aaron Matthew LeBeau
金额：
$ 34.27万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2022-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581499
关键词：
Address Adverse reactions Affinity Chromatography Animals Antibodies Binding Biochemical Biomanufacturing Biophysical Process Capsid Capsid Proteins Cell Surface Receptors Cells Clinic Clinical Trials Coupled Dependovirus Development Disease Dose Ectopic Expression Engineering Enhancers Gene Delivery Generations Genes Genetic Engineering Hereditary Disease Human Immunologic Deficiency Syndromes Infection Insertional Mutagenesis Investments Lead Libraries Machine Learning Malignant Neoplasms Malignant neoplasm of prostate Maps Mediating Molecular Monoclonal Antibodies Mus Nucleic Acid Regulatory Sequences Outcome Patients Performance Population Positioning Attribute Production Property Randomized Reporting Risk Safety Serotyping Site Specificity Structure Surface Technology Tissues Transgenes Tropism Variant Viral Viral Vector Virion Virus Work Xenograft Model cell type design gene therapy improved in vivo neutralizing antibody novel novel therapeutic intervention patient safety promoter prototype receptor scaffold technology platform technology validation therapeutically effective tissue tropism viral gene delivery virus tropism wasting

项目摘要

Project Summary Gene therapy is a promising treatment for many diseases. For gene therapy to become increasingly successful, three hurdles must be overcome: We need viral vectors that are (1) safe, (2) efficient, and (3) cell type specific. Adeno-associated virus (AAV) has emerged as a viral vector that is safe in humans, efficient at delivering transgenes to both dividing and arrested cells, and able to drive long-term expression. Unfortunately, the broad tropism of AAV is detrimental when gene delivery to specific cells (e.g., cancer) is paramount and ectopic expression in healthy cells or tissues poses a risk to the patient’s safety. We recently reported a working prototype of a novel configurable viral gene delivery technology. This technology consists of a capsid that we genetically engineer to express an adapter domain to which we covalently attach monoclonal antibodies to form antibody-AAV composites. AAV tropism is redirected toward the antibody’s cognate receptor, which is expressed on a targeted cell type, but not off-target cell populations. Here, we will take the next critical steps to build on this prototype and broaden the impact of our technology. We will improve composite-AAV formation efficiency and infectivity (Aim 1), comprehensively map additional engineerable capacity across AAV serotypes identify new capsid engineering strategies and enable machine- learning guided AAV design (Aim 2) and, as a proof of concept, determine target specificity and spread of AAV composites in vivo (Aim 3). The outcome of this work will be a validated viral vector platform technology that uses antibodies to target gene delivery to rationally identified cell types. This technology will enable fundamentally new gene therapy paradigms and, in the longer term, lead to new therapeutic approaches for inherited disorders and cancer.

项目摘要基因治疗是许多疾病的有前途疗法。为了使基因疗法变得越来越成功，必须克服三个障碍：我们需要（1）安全，（2）有效的病毒向量，并且（3）特定于细胞类型。腺相关病毒（AAV）已成为人类安全的病毒载体，有效地传递转基因对分裂和逮捕细胞，并能够驱动长期表达。不幸的是，宽阔当基因递送到特定细胞（例如癌症）至关重要时，AAV的向量是有害的在健康细胞或时机中的表达对患者的安全构成风险。我们最近报道了一种新型可构型病毒基因递送技术的工作原型。这项技术由我们一般工程师表达一个适配器域的衣壳组成，我们共价附加形成抗体-AAV组成的单克隆抗体。 AAV的向向主义重定向到抗体同源受体，该受体在靶向细胞类型上表示，但不能脱靶细胞群体。在这里，我们将采取下一个关键步骤以构建该原型并扩大我们技术的影响。我们将提高复合-AAV形成效率和感染（AIM 1），全面绘制额外跨AAV血清型的工程容量可以确定新的Capsid工程策略，并启用机器 - 学习指导AAV设计（AIM 2），作为概念证明，确定了AAV的目标特异性和传播体内复合材料（AIM 3）。这项工作的结果将是经过验证的病毒矢量平台技术，该技术使用抗体来靶向基因传递到合理鉴定的细胞类型。这项技术将使从根本上实现新的基因疗法范例从长远来看，为遗传性疾病和癌症提供了新的治疗方法。