AAV-Mediated Gene Therapy for Metabolic Bone Disease

AAV 介导的代谢性骨病基因治疗

基本信息

批准号：
7676053
负责人：
Selvarangan Ponnazhagan
金额：
$ 26.77万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7676053
关键词：
Adverse effects Affect Anabolic Agents Area Autologous Transplantation BMP2 gene Biodistribution Bone Density Bone Development Bone Marrow Bone Morphogenetic Proteins Bone Resorption Bone remodeling Cell Transplants Cells Collagen Type I Defect Dependovirus Development Disease Ectopic Expression Engraftment Etiology Event Fracture Functional disorder Future Gene Transfer Genetic Half-Life Hematologic Neoplasms Histology Home environment Homing Hormonal Human Image Immunocompetent Immunohistochemistry In Vitro Integrins Lead Luc Gene Mediating Mesenchymal Stem Cells Metabolic Metabolic Bone Diseases Metabolic Diseases Methods Mus Mutation Osteoblasts Osteoclasts Osteogenesis Osteogenesis Imperfecta Osteoporosis Outcome Study Pathogenicity Pharmaceutical Preparations Pharmacotherapy Production Proliferating Property Proteins Recombinant adeno-associated virus (rAAV)Recombinants Reporter Signal Transduction Source Spinal Fusion Stromal Cells Testing Therapeutic Effect Tissues Transgenes Viral Genes adeno-associated viral vector age related base bone bone mass bone morphogenetic protein 2 cancer cell gene therapy human disease immunogenic immunogenicity improved in vivo mouse model novel novel therapeutics older patient osteoblast differentiation osteogenic osteopontin osteoprogenitor cell pre-clinical prevent promoter research clinical testing self-renewal senescence spine bone structure therapeutic gene transgene expression vector

项目摘要

DESCRIPTION (provided by applicant): Adeno-associated virus (AAV) vectors are ideal for the long-term treatment of metabolic defects. Unique features including non-pathogenicity, low-immunogenicity and stable expression have positively resulted in successful preclinical and clinical evaluation of this vector. One of the potential, yet, unexplored areas of gene therapy using rAAV is metabolic bone defects characterized by a reduction in the mass of bone per unit volume as in osteoporosis or insufficient mechanisms for anabolic bone remodeling as in spinal fusion and fracture. Although, currently available hormonal and drug therapies for osteopenia aim to prevent further bone destruction by osteoclasts, therapies directed towards increasing bone mass by increasing the event of osteogenesis will be greatly beneficial. Treatments to increase bone density by anabolic agents are limited due to ineffective delivery methods and a short half-life of the drugs and purified proteins. Thus, novel methods to induce sustained in vivo osteogenesis should improve the pathophysiology of the disease. Our earlier studies established long-term efficacy of rAAV-transduced mesenchymal stem cells (MSC) to selectively engraft to bone, repopulate and express a transgene in a mouse model. Preliminary studies pertaining to this application indicated that recombinant AAV-2 (rAAV) transduces human and murine MSC and osteoprogenitors in high-efficiency and that rAAV-mediated transfer of bone morphogenetic protein-2 (BMP-2) leads to their differentiation into osteoblast lineage. Thus, we hypothesize that autologous transplantation of culture-expanded MSC, transduced with rAAV encoding BMP-2 under the control of osteoprogenitor-specific promoters, will result in osteoblast enrichment and increased bone mass. In the current proposal, we will evaluate this hypothesis to: 1) Determine the engraftment of ex vivo cultured MSC and optimize enrichment of homing to bone by ectopic expression of a bone homing signal, 2) Determine bone-specific expression of BMP-2 and its osteogenic significance in vivo and 3) Determine the effects of AAV-mediated gene therapy in osteopenic mice models in vivo. A successful outcome of these studies may form the basis for future development of gene therapy approaches for osteoporosis and other osteopenic diseases in humans.

描述（由申请人提供）：腺相关病毒（AAV）载体是代谢缺陷长期治疗的理想选择。非致病性、低免疫原性和稳定表达等独特特征为该载体的临床前和临床评估带来了积极的结果。使用 rAAV 进行基因治疗的潜在但尚未探索的领域之一是代谢性骨缺陷，其特征是每单位体积的骨质量减少（如骨质疏松症）或合成代谢骨重塑机制不足（如脊柱融合和骨折）。尽管目前针对骨质减少症的激素和药物疗法旨在防止破骨细胞进一步破坏骨质，但通过增加成骨事件来增加骨量的疗法将非常有益。由于递送方法无效以及药物和纯化蛋白质的半衰期短，通过合成代谢药物增加骨密度的治疗受到限制。因此，诱导持续体内成骨的新方法应该改善该疾病的病理生理学。我们早期的研究证实了 rAAV 转导的间充质干细胞 (MSC) 在小鼠模型中选择性移植到骨骼、重新增殖和表达转基因的长期功效。与该应用相关的初步研究表明，重组 AAV-2 (rAAV) 能够高效转导人和小鼠 MSC 和骨祖细胞，并且 rAAV 介导的骨形态发生蛋白 2 (BMP-2) 的转移导致它们分化为成骨细胞谱系。因此，我们假设，在骨祖细胞特异性启动子的控制下，用编码BMP-2的rAAV转导的培养扩增的MSC的自体移植将导致成骨细胞富集和骨量增加。在当前的提案中，我们将评估这一假设：1) 确定离体培养的 MSC 的植入，并通过骨归巢信号的异位表达优化归巢的富集，2) 确定 BMP-2 的骨特异性表达和其体内成骨意义；3) 确定 AAV 介导的基因治疗在体内骨质减少小鼠模型中的效果。这些研究的成功结果可能为未来开发人类骨质疏松症和其他骨质减少疾病的基因治疗方法奠定基础。