Development of AAV vectors for long-term expression of eCD4-Ig

开发用于长期表达 eCD4-Ig 的 AAV 载体

• 批准号: 9770769
• 负责人: MICHAEL DAVID ALPERT
• 金额: $ 99.97万
• 依托单位: EMMUNE, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770769
• 关键词: Affinity; Antibodies; Antibody Formation; Antibody Response; Antigen-Presenting Cells; Antiviral Agents; Binding; CCR5 gene; CMV promoter; Dependovirus; Development; Dose; Engineering; Enhancers; Enzymes; Epitopes; Exhibits; Gene Expression; Glycoproteins; Grant; HIV; HIV-1; Healthcare Systems; Human T-lymphotropic virus 1; Immune response; Immunoglobulin Constant Region; Immunoglobulin Somatic Hypermutation; Immunologics; In Vitro; Infection; Innate Immune Response; Internal Ribosome Entry Site; Intramuscular Injections; Intravenous; Introns; Laboratory Animals; Life; Longevity; Macaca; Macaca mulatta; Methylation; Muscle; Muscle Cells; Nature; Patients; Peptide Hydrolases; Plasma; Polyadenylation; Post-Translational Protein Processing; Primates; Production; Research; Risk; Simian virus 40; Site; Structure; T cell response; Testing; Time; Transgenes; Viral; Virus Receptors; adeno-associated viral vector; base; cellular transduction; cost; design; expression vector; fitness; gene transfer vector; global health; immunogenic; immunogenicity; improved; innovation; neutralizing antibody; novel; pandemic disease; peptidomimetics; prevent; promoter; protein-tyrosine sulfotransferase 2; public health relevance; receptor; simian human immunodeficiency virus; synthetic antibodies; transcription factor; transgene expression; vector; vector genome

ABSTRACT / SUMMARY / PROJECT DESCRIPTION A single intramuscular injection of an adeno-associated virus (AAV) vector that expresses eCD4-Ig has the potential to treat or prevent HIV-1 infection for a lifetime. eCD4-Ig is a synthetic antibody or “immunoadhesin” constructed by fusing parts of the viral receptor (CD4) and coreceptor (CCR5) to the constant region of an antibody. Because eCD4-Ig binds the HIV-1 envelope glycoprotein (Env) through the same contacts used by Env to recognize its receptor and coreceptor, eCD4-Ig neutralizes 100% of HIV-1 isolates and presents fundamental barriers to viral escape. We have previously shown that rhesus macaques inoculated with AAV expressing eCD4-Ig exhibited sterilizing protection against high-dose intravenous challenges with simian- human immunodeficiency virus (SHIV). Now, we propose several practical innovations designed to maximize the concentrations of eCD4-Ig in plasma that are sustained over the long term by AAV-transduced muscle.

摘要/总结/项目描述 表达eCD 4-IG的腺相关病毒（AAV）载体的单次肌内注射具有 治疗或预防HIV-1感染的潜力。eCD 4-IG是一种合成抗体或“免疫粘附素” 通过将病毒受体（CD 4）和辅助受体（CCR 5）的部分融合到一个 抗体的由于eCD 4-IG通过与HIV-1包膜糖蛋白（Env）相同的接触结合， eCD 4-IG可100%中和HIV-1分离株，并可将其与HIV-1的受体和辅助受体结合， 病毒逃逸的根本障碍我们以前已经证明，恒河猴接种AAV 表达eCD 4-IG的小鼠表现出对高剂量静脉注射猴免疫球蛋白的杀菌保护作用。 人类免疫缺陷病毒（SHIV）。现在，我们提出了几个实用的创新，旨在最大限度地提高 通过AAV转导的肌肉长期维持的血浆中eCD 4-IG的浓度。