Preclinical Studies Supporting Phase Ib Study of Minidystrophin Gene in AAV Vecto

描述（由申请人提供）：该提案旨在推进基于嵌合腺相关病毒（rAAV）的高度截断的肌营养不良蛋白（minidystrophin）基因疗法的区域递送，用于治疗杜氏肌营养不良症（DMD）。实验重点是完成启动所需的临床前研究，也是FDA推荐的Ib期桥接研究。拟议的Ib期研究区域基因递送到DMD患者的下肢。更具体地说，本文的研究评估了在大型动物模型[金毛犬肌肉萎缩模型（GRMD）和非人灵长类动物（NHP）]中使用血管介导的、区域的、孤立的下肢输注（ILP）实现的载体传递（转导电位）和表达谱。GRMD模型为研究rAAV- minidystrophin在改善DMD最接近病理对应物方面的功效提供了额外的潜力。我们的初步1期数据表明，rAAV-minidystrophin具有良好的耐受性，当直接注射到二倍体基因组时，可介导高达2.5个转基因拷贝/二倍体基因组的表达水平。此外，对GRMD和NHP的经血管肢体传递的初步研究表明，它们具有广泛的转导潜力，并持续高水平的基因表达。这些数据累积起来暗示了预期的临床前研究的积极结果，联合提议的Ib期试验是偶然的。rAAV-minidystrophin在1b期临床试验中的积极结果有望通过支持rAAV-minidystrophin区域肢体输送的II期临床试验，立即影响DMD患者。更重要的是，推进DMD的基因治疗为延长活动时间、增加运动能力和减少疾病进展提供了巨大的潜力，目前无法治愈的人群的治疗仍然是姑息性的。认识到这一潜力，并考虑到初步研究，包括临时DSMB/IDMC i期试验报告，Asklepios生物制药公司已获得MDA TRAC拨款，资助拟议研究的50%。本提案旨在推进基因疗法治疗杜氏肌营养不良症（DMD）的区域递送。实验重点是完成大型动物模型的临床前研究，这些研究需要启动也被提议和FDA推荐的Ib期桥接研究，该研究涉及到DMD患者下肢的区域基因传递。推进DMD的基因治疗为改善目前无法治愈的人群的生活质量提供了巨大的潜力，这些人群的治疗仍然是姑息性的。

DESCRIPTION (provided by applicant): This proposal intends to advance the regional delivery of a chimeric adeno-associated virus (rAAV)-based, highly-truncated dystrophin (minidystrophin) gene therapy for the treatment of Duchenes Muscular Dystrophy (DMD). Experiments focus on completing preclinical studies required to initiate, the also proposed, FDA recommended Phase Ib bridging study. The proposed Phase Ib investigates regional gene delivery to the lower extremities of DMD patients. More specifically, the studies herein evaluate vector delivery (transduction potential) and expression profiles achieved using blood vessel-mediated, regional, isolated lower limb infusion (ILP) in large animal models [the Golden Retriever Muscular Dystrophy model (GRMD) and non-human primates (NHP)]. The GRMD model offers the additional potential to investigate the efficacy of rAAV- minidystrophin in ameliorating the nearest pathological counterpart of DMD. Our preliminary Phase 1 data indicate rAAV-minidystrophin is well tolerated and mediates expression levels as high as 2.5 transgene copies/diploid genome when directly injected in the bicep. Additionally, initial investigations of tranvascular limb delivery in GRMD and NHP demonstrate widespread transduction potential, and sustained high levels of gene expression. These data cumulatively allude to the positive outcomes expected from the proposed preclinical studies on which the jointly proposed Phase Ib trial is contingent. A positive outcome of rAAV-minidystrophin in Phase 1b clinical trials is expected to immediately impact DMD patients by supporting Phase II clinical trials of regional limb delivery of rAAV-minidystrophin. More importantly advancing a gene therapy for DMD offers the significant potential for prolonged ambulation, increased exercise capacity, and reduced disease progression to a currently incurable population whose treatments remain palliative. In recognition of this potential and in light of the preliminary studies including an Interim DSMB/IDMC Phase Ia trial report, Asklepios Biopharmaceutical has been awarded an MDA TRAC grant funding 50% of the proposed studies. This proposal intends to advance the regional delivery of a gene therapy for the treatment of Duchenes Muscular Dystrophy (DMD). Experiments focus on completing preclinical studies in large animal models that are required to initiate, the also proposed and FDA recommended, Phase Ib bridging study that involves regional gene delivery to the lower extremities of DMD patients. Advancing a gene therapy for DMD offers the significant potential for improved quality of life to a currently incurable population whose treatments remain palliative.