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

支持 AAV Vecto 中微型肌营养不良蛋白基因的 Ib 期研究的临床前研究

• 批准号: 7692195
• 负责人: Scott William John McPhee
• 金额: --
• 依托单位: ASKLEPIOS BIOPHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2011-05-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7692195
• 关键词: Adverse event; Animal Model; Animal Testing; Anterior; Award; Biological Assay; Biological Products; Blood Vessels; Canis familiaris; Clinical; Clinical Trials; Complex; Data; Dependovirus; Development; Diploidy; Disease Progression; Distal; Dose; Duchenne muscular dystrophy; Dystrophin; Dystrophin-Associated Proteins; Exercise; Feasibility Studies; Fibrosis; Flexor; Funding; Gastrocnemius Muscle; Gene Delivery; Gene Expression; Gene Transfer; Genes; Genome; Grant; Infusion procedures; Investigation; Isometric Exercise; Lateral; Leg; Light; Limb structure; Lower Extremity; Medial; Mediating; Methods; Modeling; Molecular Profiling; Mus; Muscle; Muscle Fibers; Muscular Dystrophies; Outcome; Patients; Pelvis; Performance; Phase; Phase II Clinical Trials; Phenotype; Population; Protocols documentation; Quality of life; Reporting; Safety; Sarcoglycans; Sarcolemma; Serious Adverse Event; Skeletal Muscle; Small Business Innovation Research Grant; Staining method; Stains; System; Testing; Therapeutic; Therapeutic Effect; Toxicology; Transgenes; Translating; base; biceps brachii muscle; expectation; extensor digitorum; gene therapy; improved; meetings; mini-dystrophin; nonhuman primate; palliative; phase 2 study; pre-clinical; preclinical study; rectus femoris; research study; response; success; tibialis anterior muscle; vector

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.

描述（由申请人提供）：该提案旨在促进基于嵌合腺相关病毒（rAAV）的高度截短肌营养不良蛋白（minidystrophin）基因疗法的区域递送，用于治疗杜兴氏肌营养不良症（DMD）。实验重点是完成启动FDA推荐的Ib期桥接研究所需的临床前研究。拟议的Ib期研究DMD患者下肢的区域基因递送。更具体地，本文的研究评估了在大型动物模型[金毛猎犬肌营养不良模型（GRMD）和非人灵长类动物（NHP）]中使用血管介导的、区域性的、分离的下肢输注（ILP）实现的载体递送（转导潜力）和表达谱。GRMD模型提供了额外的潜力来研究rAAV-小型肌萎缩蛋白在改善DMD的最接近的病理对应物中的功效。我们的初步1期数据表明，rAAV-小型肌萎缩蛋白是良好耐受的，并且当直接注射到二头肌中时，介导高达2.5转基因拷贝/二倍体基因组的表达水平。此外，GRMD和NHP中经血管肢体递送的初步研究表明广泛的转导潜力和持续的高水平基因表达。这些数据累积暗示了联合拟定的Ib期试验所依赖的拟定临床前研究的预期积极结局。1b期临床试验中rAAV-小型肌萎缩蛋白的积极结果预计将通过支持rAAV-小型肌萎缩蛋白的局部肢体递送的II期临床试验立即影响DMD患者。更重要的是，推进DMD的基因治疗为延长截肢时间、增加运动能力和减少目前无法治愈的人群的疾病进展提供了巨大的潜力，这些人群的治疗仍然是姑息性的。认识到这一潜力，并根据初步研究，包括中期DSMB/IDMC Ia期试验报告，Asklepios生物制药已被授予MDA TRAC赠款资助50%的拟议研究。该提案旨在推进用于治疗Duchenes肌营养不良症（DMD）的基因疗法的区域递送。实验重点是完成大型动物模型中的临床前研究，这些研究需要启动，也是FDA建议的，Ib期桥接研究，涉及DMD患者下肢的区域基因递送。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。