Novel Gene Therapy for Critical Limb Ischemia and Limb Salvage in Vascular Occlusive Disease

针对血管闭塞性疾病严重肢体缺血和保肢的新型基因疗法

基本信息

批准号：
10447520
负责人：
ZHAO-JUN LIU
金额：
$ 53.33万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-24 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447520
关键词：
Amputation Angiogenic Factor Angioplasty Animal Experimentation Animals Arteries Atherectomy Atherosclerosis Biodistribution Biological Biological Assay Blood Blood Tests Blood Vessels Blood capillaries Blood flow Bypass Caring Cell Adhesion Molecules Cell Communication Cell physiology Cells Cellular Morphology Clinical Clinical Trials Data Development Disease Docking Dose E-Selectin Endothelial Cells Face Fibrin fragment D Fibroblast Growth Factor Foundations Funding Future Gangrene Gene Delivery Generations Goals Harvest Health Care Costs Homing Human In Vitro Inflammation Intervention Ischemia Isolated limb perfusion Ligands Limb Salvage Limb structure Long-Term Effects Mechanics Medical Metabolic Modeling Mus Muscle Cells Muscle Fibers National Heart, Lung, and Blood Institute Natural regeneration Organ Pain Pain in lower limb Paracrine Communication Pathologic Patients Peripheral arterial disease Phase Physical Function Pilot Projects Plasmids Process Protocols documentation Recovery Renal function Research Rest Running Safety Salvage Therapy Serum Site Skeletal Muscle Stains Stents Structure Testing Therapeutic Therapeutic Effect Thrombosis Tissues Toxic effect Transgenes Tumor-infiltrating immune cells Vascular Endothelial Growth Factors Viral Walking Work adenoviral-mediated angiogenesis artery occlusion base clinically relevant critical limb Ischemia delivery vehicle efficacy validation endothelial stem cell experience gene delivery system gene therapy healing high risk human study improved in vivo innovation intercellular communication limb amputation limb ischemia limb loss liver function mortality risk mouse model neovascularization non-healing wounds novel novel therapeutics preclinical study prevent progenitor recruit regenerative regenerative cell repaired scale up skin ulcer stability testing stem stem cells success systemic toxicity therapeutic angiogenesis tissue regeneration tissue repair translational research program treadmill treatment optimization vector

Amputation Angiogenic Factor Angioplasty Animal Experimentation Animals Arteries Atherectomy Atherosclerosis Biodistribution Biological Biological Assay Blood Blood Tests Blood Vessels Blood capillaries Blood flow Bypass Caring Cell Adhesion Molecules Cell Communication Cell physiology Cells Cellular Morphology Clinical Clinical Trials Data Development Disease Docking Dose E-Selectin Endothelial Cells Face Fibrin fragment D Fibroblast Growth Factor Foundations Funding Future Gangrene Gene Delivery Generations Goals Harvest Health Care Costs Homing Human In Vitro Inflammation Intervention Ischemia Isolated limb perfusion Ligands Limb Salvage Limb structure Long-Term Effects Mechanics Medical Metabolic Modeling Mus Muscle Cells Muscle Fibers National Heart, Lung, and Blood Institute Natural regeneration Organ Pain Pain in lower limb Paracrine Communication Pathologic Patients Peripheral arterial disease Phase Physical Function Pilot Projects Plasmids Process Protocols documentation Recovery Renal function Research Rest Running Safety Salvage Therapy Serum Site Skeletal Muscle Stains Stents Structure Testing Therapeutic Therapeutic Effect Thrombosis Tissues Toxic effect Transgenes Tumor-infiltrating immune cells Vascular Endothelial Growth Factors Viral Walking Work adenoviral-mediated angiogenesis artery occlusion base clinically relevant critical limb Ischemia delivery vehicle efficacy validation endothelial stem cell experience gene delivery system gene therapy healing high risk human study improved in vivo innovation intercellular communication limb amputation limb ischemia limb loss liver function mortality risk mouse model neovascularization non-healing wounds novel novel therapeutics preclinical study prevent progenitor recruit regenerative regenerative cell repaired scale up skin ulcer stability testing stem stem cells success systemic toxicity therapeutic angiogenesis tissue regeneration tissue repair translational research program treadmill treatment optimization vector

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项目摘要

Project Summary/Abstract: Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease (PAD). It manifests with leg pain, decreased walking distance, non-healing wounds and gangrene. About 1/3 of CLI patients don't respond to standard therapy and ultimately undergo major limb amputation. This critical unmet need demands a solution. CLI causes >105 major limb amputations in the USA per year. Our overarching goal is to develop a novel limb-salvage therapy. Gene therapy is a promising option to induce therapeutic angiogenesis, increasing blood flow in ischemic limbs for repair. This approach has raised a great deal of hope for `no-option' CLI patients. However, previous gene therapy approaches using naked plasmids encoding angiogenic factors, such as VEGF and FGF, failed to show substantial clinical benefits. Moreover, early adenovirus-mediated gene delivery systems raised concerns over safety. Hence, more efforts for the identification of alternative effective transgenes and safe/efficient delivery vectors are crucial. Success of gene therapy for CLI requires activation and participation of endogenous healing mechanisms including recruitment/homing of stem/progenitor cells to ischemic tissue. Enhanced recruitment/homing depends upon a `hospitable' tissue microenvironment that is receptive of endogenous regenerative cells. Our previous research discovered that in ischemia, homing for these critical repair cells relies on specific cell-cell interactions via a panel of adhesion molecules, including E- selectin/ligand pairs. The levels of vascular E-selectin in the ischemic limb tissues is down-regulated. We hypothesize that E-selectin is pivotal in the recruitment of stem/progenitor cells necessary for neovascularization in ischemic tissues. E-selectin can serve as a docking site for endogenous stem/progenitor cells to anchor. The resulting downstream cell-cell signaling cascades can increase angiogenesis and tissue repair/regeneration. We have recently demonstrated feasibility, safety and superior efficacy of E-selectin/AAV- based gene therapy for improving limb perfusion, increasing neovascularization, decreasing ischemia, reducing gangrene, minimizing tissue damage, augmenting regeneration of the ischemic skeletal muscle, and extending running capacity, in murine models. In the clinical setting, we believe that such biologic effects can increase functional walking capacity and prevent limb loss. We thus propose to induce a supportive tissue microenvironment by priming endothelial cells in capillaries and other ischemic limb-tissue cells with the adhesion molecule, E-selectin, using a safe and efficient AAV2 vector. We will utilize a clinically relevant mouse model of CLI – the footpad gangrene, to test this novel gene therapy. The objectives are to validate and optimize the translational protocol for a future large-animal pre-clinical study and conduct the requisite IND-enabling GLP/GMP animal research for a subsequent pilot human study. The development of this novel gene therapy may ultimately eliminate the need for most amputations by accelerating therapeutic angiogenesis and tissue regeneration, and promises to revolutionize the treatment for PAD/CLI patients.

项目摘要/摘要：临界肢体缺血（CLI）是周围动脉疾病（PAD）最先进的阶段。它表现出来腿痛，步行距离减少，伤口非愈合和坏疽。大约1/3的CLI患者不对标准疗法做出反应，并最终接受主要的肢体截肢。这个关键的未满足需求需求解决方案。 CLI每年在美国> 105个主要肢体截肢。我们的总体目标是开发新型的肢体水文疗法。基因疗法是诱导治疗血管生成，增加的有望选择缺血性四肢的血流进行修复。这种方法对“无选” CLI患者产生了巨大的希望。但是，以前的基因疗法使用编码血管生成因子的裸质粒，例如 VEGF和FGF未能显示出可观的临床益处。此外，早期腺病毒介导的基因输送系统引起了人们对安全的关注。因此，为识别替代有效的更多努力转基因和安全/有效的递送向量至关重要。基因疗法的CLI成功需要激活并参与内源性愈合机制，包括招募/祖祖细胞募集/归巢缺血组织。增强的招聘/归宿取决于“好客”的组织微环境接受内源性再生细胞。我们以前的研究发现，在缺血中，这些临界修复细胞依赖于特定的细胞 - 细胞相互作用，包括粘合分子，包括e- selectin/配体对。缺血性肢体组织中血管E-选择素的水平下调。我们假设电子选择素在募集的茎/祖细胞中至关重要缺血组织中的新血管化。电子选择素可以用作内源性茎/祖细胞的对接位点细胞锚定。产生的下游细胞 - 细胞信号传导级联反应会增加血管生成和组织维修/再生。最近，我们证明了电子选蛋白/AAV-的可行性，安全性和效率基于基因疗法，用于改善肢体灌注，增加新血管形成，减少缺血，减少坏疽，最小化组织损伤，增加缺血性骨骼肌的再生，并延伸跑步能力，在鼠模型中。在临床环境中，我们认为这种生物学作用可以增加功能性步行能力并防止肢体损失。因此，我们建议诱导支撑组织毛细血管和其他缺血性肢体组织细胞中启动内皮细胞的微环境与使用安全有效的AAV2载体，粘附分子E-选择素。我们将利用临床相关的鼠标 CLI的模型 - 脚PAD分泌，以测试这种新型基因疗法。目标是验证和优化未来大动画前研究的翻译方案，并进行必要的索引 GLP/GMP动物研究，用于随后的试验人类研究。这种新型基因疗法的发展最终可以通过加速治疗性血管生成和组织来消除大多数截肢的需求再生，并有望改变PAD/CLI患者的治疗方法。