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

项目总结： 这项提案针对的是AAV介导的基因疗法翻译中的一个关键挑战，即广泛存在的 人类体内已存在的α病毒抗体(Abs)。预先存在的α病毒抗体阻止病毒载体进入和 转导靶细胞。目前，只有α抗体阴性的个体才有资格接受AAVs基因治疗 治疗，因为没有有效的方法来克服这一挑战。我们最近出版的 研究表明，需要广泛的免疫靶向才能通过免疫有效地消除抗体 抑制(IS)和确定一种有效的IS抗体耗竭方法，在小鼠模型中，使用联合 雷帕霉素和强的松龙。然而，这是养生法需要长达8-12周的每日服药。 链球菌的免疫球蛋白降解酶(IDES)是一种特异性地裂解免疫球蛋白的半胱氨酸蛋白酶 分子。大量研究表明，在动物体内，IDES能快速有效地降解免疫球蛋白。 在人类身上，支持IDE的治疗潜力。IDES的半衰期较短，为4.9±2.8小时 表现出剂量限制毒性。因此，我们假设，IV IDES政府可能会提供一种新的 克服现有的αAAV-Ig G的工具，用于rAAV介导的基因治疗。这项建议是为了开发一种 有效转导rAAV基因治疗疾病的一种新的有效的AB耗竭方法 临床，使用MPS IIIB的小鼠模型，MPS IIIB是一种毁灭性的神经病理性溶酶体储存疾病，对其 治疗目前是可用的。利用IDES证明的快速有效的抗体去除，这 该提案将导致开发一种新的方法来有效地耗尽先前存在的α抗病毒抗体， 这可能使所有有需要的患者都有资格接受AAV基因治疗，以及一般的病毒基因治疗。我们 因此，我认为IDE可能会为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。

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.