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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.

项目概要基因疗法是治疗许多疾病的一种有前景的方法。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）高效、（3）细胞类型特异性的病毒载体。腺相关病毒 (AAV) 已成为一种对人类安全、能有效传递病毒的病毒载体转基因到分裂和停滞的细胞，并能够驱动长期表达。不幸的是，广泛当基因传递到特定细胞（例如癌症）至关重要且异位时，AAV 的趋向性是有害的在健康细胞或组织中的表达会对患者的安全构成风险。我们最近报道了一种新型可配置病毒基因传递技术的工作原型。这项技术由我们通过基因工程改造的衣壳组成，以表达我们共价附着的接头结构域单克隆抗体形成抗体-AAV 复合物。 AAV 的趋向性被重定向至抗体的同源受体，在目标细胞类型上表达，但不在目标细胞群上表达。在这里，我们将采取接下来的关键步骤来构建这个原型并扩大我们技术的影响。我们将提高复合 AAV 的形成效率和感染性（目标 1），全面绘制额外的图谱跨 AAV 血清型的可工程能力确定新的衣壳工程策略并启用机器学习引导 AAV 设计（目标 2），并作为概念证明，确定 AAV 的目标特异性和传播体内复合材料（目标 3）。这项工作的成果将是一种经过验证的病毒载体平台技术，该技术使用抗体来靶向基因递送至合理识别的细胞类型。这项技术将从根本上实现新的基因治疗范例从长远来看，这将为遗传性疾病和癌症带来新的治疗方法。