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: 7540342
• 负责人: Scott William John McPhee
• 金额: $ 32.1万
• 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 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7540342
• 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; 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; Personal Satisfaction; Phase; Phase II Clinical Trials; Phenotype; Population; Protocols documentation; Quality of life; Reporting; Safety; Sarcoglycans; Sarcolemma; Serious Adverse Event; Skeletal Muscle; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Staining method; Stains; System; Testing; Therapeutic; Therapeutic Effect; Toxicology; Transgenes; Translating; United States Food and Drug Administration; base; biceps brachii muscle; expectation; gene therapy; improved; mini-dystrophin; nonhuman primate; pre-clinical; preclinical study; research study; response; success; 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)：这项建议旨在推进嵌合腺相关病毒(RAAV)为基础的、高度截断的抗肌营养不良蛋白(Minidystrophin)基因疗法的区域交付，用于治疗Duchenes肌营养不良症(DMD)。实验的重点是完成启动所需的临床前研究，也是FDA建议的Ib期桥接研究。拟议的Ib阶段研究区域基因传递到DMD患者的下肢。更具体地说，这里的研究评估了在大型动物模型[金毛犬肌营养不良模型(GRMD)和非人灵长类动物(NHP)]中，使用血管介导的局部隔离下肢输注(ILP)实现的载体传递(转导潜力)和表达谱。GRMD模型提供了额外的潜力来研究rAAV-minidystrophin在改善最近的DMD病理对应物方面的有效性。我们的初步第一阶段数据表明，rAAV-minidystrophin具有良好的耐受性，当直接注射到二倍体二头肌中时，表达水平高达2.5个转基因拷贝/二倍体基因组。此外，GRMD和NHP经血管传递肢体的初步研究表明，GRMD和NHP具有广泛的转导潜力，并持续高水平的基因表达。这些数据累积地暗示了联合提议的Ib期试验所依据的拟议的临床前研究预期的积极结果。RAAV-minidystrophin在1b期临床试验中的积极结果预计将通过支持rAAV-minidystrophin区域肢体递送的第二阶段临床试验而立即影响DMD患者。更重要的是，推进DMD的基因治疗为延长步行时间、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治疗。认识到这一潜力，并考虑到初步研究，包括一份临时的DSMB/IDMC第一阶段试验报告，Asklepios生物制药公司已获得MDA TRAC赠款，为拟议研究提供50%的资金。这项建议旨在推进治疗杜氏肌营养不良症(DMD)的基因疗法的地区性交付。实验的重点是在大型动物模型上完成临床前研究，这些研究需要启动也被提议和FDA推荐的Ib期桥接研究，该研究涉及将基因区域性输送到DMD患者的下肢。推进DMD的基因治疗，为目前无法治愈、治疗仍是姑息性治疗的人群提供了改善生活质量的巨大潜力。