Engineering AAV capsids for enhanced transduction of skeletal muscle

工程化 AAV 衣壳以增强骨骼肌的转导

• 批准号: 10290483
• 负责人: CHARLES Corbin BAILEY
• 金额: $ 3.21万
• 依托单位: EMMUNE, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10290483
• 关键词: Adjuvant; Aducanumab; Alzheimer' s Disease; Animals; Antibodies; Antibody Response; Biological; Blood Glucose; Capsid; Capsid Proteins; Cardiovascular Diseases; Cell Culture Techniques; Clinical; Clinical Trials; Dangerousness; Dependovirus; Detection; Disease; Dose; Duchenne muscular dystrophy; Engineering; Enzyme-Linked Immunosorbent Assay; Factor IX; Gene Delivery; Gene Transduction Agent; Genetic; Goals; Grant; HIV; Human; Image; Immune response; Immunoglobulin Variable Region; In Vitro; Injections; Insulin; Insulin Receptor; Intramuscular; Intravenous; Life; Luciferases; Mediating; Modeling; Modification; Monitor; Monoclonal Antibodies; Mus; Muscle; Muscle Fibers; Patients; Pattern; Pharmaceutical Preparations; Phase II Clinical Trials; Protein Deficiency; Proteins; Protocols documentation; Recombinant adeno-associated virus (rAAV); Risk; Rodent; Safety; Serum; Serum Proteins; Site; Skeletal Muscle; Stains; Testing; Therapeutic; Therapeutic Agents; Time; Tissue Sample; Tissues; Transgenes; Translating; Tropism; Variant; Virus Inhibitors; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; base; blood glucose regulation; cellular transduction; clinically relevant; design; experimental study; frontier; gene therapy; immunogenic; immunoreaction; improved; inhibitor/antagonist; lipoprotein lipase; mini-dystrophin; neutralizing antibody; nonhuman primate; peptidomimetics; phase I trial; pre-clinical; prototype; receptor binding; success; therapeutic target; therapeutic transgene; transduction efficiency; transgene expression; vector

ABSTRACT We are developing an improved adeno-associated virus (AAV)-based gene therapy vector that we call “enhanced AAV” or “eAAV” for short. eAAV is specifically designed for gene delivery to skeletal muscle tissue. Based on preliminary studies in mice we expect it will be approximately 100 times more effective than the recombinant AAVs (rAAV1 and rAAV8) used in recent clinical trials. This gain in efficiency should allow us to achieve far higher levels of therapeutic transgene products, either directly, due to increased transduction efficiency, or indirectly, by allowing us to use less vector and thereby reduce the likelihood of host immune responses to the transgene product. The aims of this grant are threefold. Aim 1 is to finalize the design of the eAAV product in cell culture and rodent studies. Aim 2 is to test the final eAAV product in nonhuman primates, and Aim 3 is to determine whether or not it poses any unique safety risks compared to other rAAV vectors. Aim 2 comprises the bulk of the project. Here we will compare eAAV to rAAV for its ability to express both alpha-1 antitrypsin (AAT) and the human immunodeficiency virus (HIV)-inhibitor eCD4 from skeletal muscle. Achieving therapeutic levels of AAT would allow for a permanent cure of genetic AAT-deficiency while achieving reliably high levels of eCD4 expression would enable a one-shot, potentially life-long treatment for HIV.

抽象的 我们正在开发一种改进的基于腺相关病毒（AAV）的基因治疗载体 我们称之为“增强型AAV”或简称“eAAV”，是专门针对基因设计的。 根据对小鼠的初步研究，我们预计它将被输送到骨骼肌组织。 比用于的重组 AAV（rAAV1 和 rAAV8）有效约 100 倍 最近的临床试验中，这种效率的提高应该使我们能够达到更高的水平。 治疗性转基因产品，无论是由于转导效率的提高而直接产生，还是 间接地，通过允许我们使用更少的载体，从而降低宿主免疫的可能性 对转基因产物的反应。 这笔赠款的目的有三个：目标 1 是完成 eAAV 产品的设计。 目标 2 是在非人类灵长类动物中测试最终的 eAAV 产品。 目标 3 是确定与其他产品相比是否会带来任何独特的安全风险 rAAV 载体。目标 2 构成了该项目的大部分内容。在这里，我们将比较 eAAV 和 rAAV。 其表达 α-1 抗胰蛋白酶 (AAT) 和人类免疫缺陷病毒的能力 来自骨骼肌的 (HIV) 抑制剂 eCD4 可以达到 AAT 的治疗水平。 永久治愈遗传性 AAT 缺陷，同时实现可靠的高水平 eCD4 表达将使艾滋病毒的一次性、可能终身治疗成为可能。