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: 10576418
• 负责人: MICHAEL DAVID ALPERT
• 金额: $ 101.22万
• 依托单位: EMMUNE, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10576418
• 关键词: Adjuvant; Aducanumab; Alzheimer' s Disease; Animals; Antibodies; Antibody Response; Biological; Biological Products; 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; Fasting; Gene Delivery; Gene Transduction Agent; Genetic; Goals; Grant; HIV; Human; Immune response; In Vitro; Injections; Insulin; Insulin Receptor; Intramuscular; Luciferases; Mediating; Modeling; Modification; Monitor; Monoclonal Antibodies; Mus; Muscle; Muscle Fibers; Patients; Pattern; Pharmaceutical Preparations; Phase II Clinical Trials; Protein Secretion; 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; bioluminescence imaging; blood glucose regulation; cellular transduction; clinically relevant; design; experimental study; frontier; gene product; gene therapy; immunogenic; immunoreaction; improved; inhibitor; intravenous administration; lipoprotein lipase; mini-dystrophin; neutralizing antibody; nonhuman primate; peptidomimetics; phase I trial; pre-clinical; prototype; receptor binding; safety assessment; 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 我们正在开发改进的基于腺体相关的病毒（AAV）基因治疗载体 简而言之，我们称之为“增强的AAV”或“ EAAV”。 EAAV专为基因设计 传递到骨骼肌组织。基于在小鼠中的初步研究，我们希望它将是 在使用中使用的重组AAV（RAAV1和RAAV8）的效率约为100倍 最近的临床试验。这种效率的增长应该使我们能够达到更高的水平 由于转移效率的提高或 间接地，通过允许我们使用较少的向量，从而减少了宿主免疫的可能性 对转换产品的响应。 这笔赠款的目的是三倍。 AIM 1是最终确定EAAV产品的设计 细胞培养和啮齿动物研究。 AIM 2是测试非人类隐私的最终EAAV产品， AIM 3是确定与其他相比，它是否构成任何独特的安全风险 Raav矢量。 AIM 2包括项目的大部分。在这里，我们将Eaav与Raav进行比较 它具有表达α-1抗胰蛋白酶（AAT）和人类免疫缺陷病毒的能力 （HIV） - 骨骼肌的抑制剂ECD4。达到AAT的治疗水平将允许 永久治愈遗传AAT缺陷，同时可靠地达到高水平的ECD4 表达将使艾滋病毒单次，潜在的终身治疗方法。