Evolving High Potency AAV Vectors for Neuromuscular Genome Editing

进化用于神经肌肉基因组编辑的高效 AAV 载体

• 批准号: 10465740
• 负责人: Aravind Asokan
• 金额: $ 83.36万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10465740
• 关键词: Evolving; Potency; AAV; Vectors; Neuromuscular

ABSTRACT Recombinant adeno-associated viruses (AAV) have emerged as safe and effective vectors for clinical gene therapy applications including systemic treatment of neuromuscular diseases such as Spinal Muscular Atrophy (SMA), Duchenne Muscular Dystrophy (DMD), and Giant Axonal Neuropathy (GAN) amongst others. However, enabling gene editing therapeutics to treat human disease requires improved systems that achieve effective genome editing at low systemic AAV vector doses in multiple animal models. Additionally, the ideal target cell types for gene editing, including progenitor cells, are distinct from the target cells that conventional gene delivery vectors have been optimized for. Genome editing in neuromuscular tissue, in particular, is challenging. To date, no effective non-viral delivery vehicles have been identified for widespread genome editing in musculoskeletal and neurological tissue following systemic administration. Further, in case of AAV vectors, several challenges pertinent to delivery of genome editors remain. The rationale for our current proposal stems from barriers posed by (i) species-related differences observed in AAV tropism, (ii) presence of pre-existing neutralizing antibodies to natural AAV, (iii) the need for high systemic AAV doses to achieve neuromuscular gene transfer, (iv) vector dose-related toxicity as indicated by detection of liver transaminases in patients, and (v) the unique opportunity to correct progenitor cells in situ. To address these aspects, we have assembled a collaborative team with cross- cutting expertise and developed a comprehensive and innovative approach to evolve high potency AAV variants for systemic neuromuscular genome editing. Specifically, we will focus our efforts on evolving high potency AAV vectors for neuromuscular genome editing using a three-tiered approach applied across different species, tissues and cell types.

抽象的 重组腺相关病毒（AAV）已成为临床基因的安全有效向量 治疗应用，包括全身治疗神经肌肉疾病，例如脊柱肌肉萎缩 （SMA），Duchenne肌肉营养不良（DMD）和巨大的轴突神经病（GAN）等。然而， 使基因编辑治疗药物治疗人类疾病需要改进的系统，以实现有效 在多种动物模型中，基因组编辑在低系统性AAV载体剂量下。另外，理想的目标细胞 用于基因编辑的类型，包括祖细胞，与常规基因递送的靶细胞不同 向量已被优化。尤其是神经肌肉组织中的基因组编辑是具有挑战性的。迄今为止， 尚未确定有效的非病毒递送车，用于肌肉骨骼中的广泛基因组编辑 全身给药后的神经组织。此外，对于AAV向量，有几个挑战 与基因组编辑的交付有关。我们当前提议的理由来自于壁垒 通过（i）在AAV偏向主义中观察到的与物种相关的差异，（ii）存在预先存在的中和抗体 对天然AAV，（iii）需要高全身性AAV剂量以实现神经肌肉基因转移，（iv）载体 与剂量有关的毒性，如检测患者肝转氨酶的指示，（v）独特的机会 原位纠正祖细胞。为了解决这些方面，我们已经与Cross组合了一个合作团队 削减专业知识，并开发了一种全面，创新的方法来发展高效力AAV变体 用于全身神经肌肉基因组编辑。具体来说，我们将集中精力致力于发展高效力AAV 神经肌肉基因组编辑的载体，使用在不同物种（组织）上应用的三层方法 和细胞类型。