Rapid Transient Depletion of Pre-existing Antibodies for rAAV Gene Delivery

快速瞬时消耗 rAAV 基因传递的现有抗体

• 批准号: 9807279
• 负责人: HAIYAN FU
• 金额: $ 23.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-12 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807279
• 关键词: Animals; Antibodies; Antibody Suppression; Blocking Antibodies; Brain; Caspase; Cells; Child; Cleaved cell; Clinic; Data; Dependovirus; Development; Disease; Dose; Dose-Limiting; Enzymes; Excision; Gene Delivery; Goals; Half-Life; High Prevalence; Histopathology; Human; Immune Targeting; Immunoglobulin G; Immunosuppression; Individual; Injections; Lysosomal Storage Diseases; Mediating; Modeling; Mucopolysaccharidosis III B; Mus; Neuropathy; Pathology; Patients; Peripheral; Population; Publishing; Recombinant adeno-associated virus (rAAV); Regimen; Sirolimus; Streptococcus; Testing; Therapeutic; Tissues; Toxic effect; Translations; Viral Genes; Viral Vector; adeno-associated viral vector; base; clinical application; clinically relevant; experimental study; gene therapy; mouse model; novel; novel strategies; prednisolone; tool; vector; vector biodistribution

Project Summary: This proposal targets a critical challenge in the translation of AAV-mediated gene therapy, the widespread pre-existing αAAV antibodies (Abs) in humans. Pre-existing αAAV-Abs block AAV vectors from entering and transducing target cells. Currently, only αAAV-Abs-negative individuals are eligible for AAV-gene therapy treatment, because no effective approach is available to overcome this challenge. Our recently published studies demonstrated that broad immune targeting is required for effective Ab-depletion by immune suppression (IS) and identified an effective IS Ab-depletion approach in a mouse model, using combination of rapamycin and prednisolone. However, this IS regimen requires up to 8-12-week-long daily administration. The IgG degrading enzymes of Streptococci (IdeS) are cysteine proteases that specifically cleaves IgG molecules. Numerous studies have demonstrated rapid and effective IgG degradation by IdeS in animals and in humans, supporting the therapeutic potential of IdeS. IdeS has a short half-life of 4.9±2.8hr with no demonstrated dose limiting toxicity. We therefore hypothesize that IV IdeS administration may offer a novel tool to overcome the pre-existing αAAV-IgG for rAAV-mediated gene therapy. This proposal is to develop a novel effective ab-depletion approach for the effective translation of rAAV gene therapy to treat diseases in clinic, using a mouse model of MPS IIIB, a devastating neuropathic lysosomal storage disease, for which not treatment is currently available. Taking advantage of demonstrated rapid effective Ab removal by IdeS, this proposal will lead to the development of a novel approach for effective depletion of pre-existing αAAV-Abs, which may make all patients in need eligible to AAV gene therapy, and viral gene therapy in general. We therefore believe that IdeS may offer the answer to the challenge posed by pre-existing Abs to the translation of gene therapy products using AAV and other viral vectors.

项目概要： 该提案针对的是 AAV 介导的基因疗法转化中的一个关键挑战，该疗法是广泛应用的基因疗法。 人类体内预先存在的 αAAV 抗体 (Ab) 会阻止 AAV 载体进入和传播。 目前，只有 αAAV-Abs 阴性个体才有资格接受 AAV 基因治疗。 治疗，因为没有有效的方法可以克服这一挑战。 研究表明，通过免疫有效消除抗体需要广泛的免疫靶向 抑制 (IS) 并在小鼠模型中确定了一种有效的 IS Ab 耗竭方法，使用组合 然而，这种 IS 方案需要长达 8-12 周的每日给药。 链球菌的 IgG 降解酶（IdeS）是专门裂解 IgG 的半胱氨酸蛋白酶 大量研究表明 IdeS 在动物和动物体内可快速有效地降解 IgG。 在人体中，支持 IdeS 的治疗潜力，其半衰期较短，为 4.9±2.8 小时。 因此，我们证明 IV IdeS 给药可能提供一种新颖的方法。 克服 rAAV 介导的基因治疗中现有的 αAAV-IgG 的工具。 有效转化 rAAV 基因疗法治疗疾病的新型有效 ab 消除方法 诊所使用 MPS IIIB 小鼠模型，这是一种毁灭性的神经性溶酶体贮积病， 目前可以利用 IdeS 快速有效去除抗体的治疗方法。 该提案将导致开发一种有效消除先前存在的 αAAV-Ab 的新方法， 这可能使所有有需要的患者都有资格接受 AAV 基因治疗和一般病毒基因治疗。 因此相信 IdeS 可以为现有 Abs 给翻译带来的挑战提供答案 使用 AAV 和其他病毒载体的基因治疗产品。