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Genetic engineering of kidney allografts by ex vivo perfusion delivery of adeno-associated viral vectors

通过腺相关病毒载体的离体灌注递送同种异体肾的基因工程

基本信息

批准号：
10480356
负责人：
Aravind Asokan
金额：
$ 48.3万
依托单位：
DUKE UNIVERSITY
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：
2022-07-19 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10480356
关键词：
Address Adenovirus Vector Allografting Autologous Transplantation Cells Chronic Clinical Cryopreservation Development End stage renal failure Engineering Evolution Family suidae Gene Delivery Gene Transduction Agent Genes Genetic Engineering Goals Graft Survival Green Fluorescent Proteins Heart Transplantation Human Immune Immune response Immunologics Immunosuppression Individual Injury Kidney Kidney Transplantation Libraries Longevity Lung Transplantation Mediating Methods Modeling Organ Organ Donor Organ Transplantation Outcome Patients Perfusion Pre-Clinical Model Process Rattus Regimen Reporter Reporter Genes Research Research Personnel Safety Solid System Testing Time Transgenes Transplantation Tropism United States Viral Virus Work adeno-associated viral vector allotransplant cell type clinical development clinical translation clinically relevant cross reactivity design ex vivo perfusion experimental study gene therapy graft function heart allograft high risk immunogenicity immunoregulation improved improved functioning kidney allograft liver transplantation nonhuman primate novel novel strategies organ repair overexpression post-transplant programmed cell death ligand 1 rational design response single-cell RNA sequencing targeted delivery therapeutic gene transgene delivery transgene expression transplant model uptake

项目摘要

Abstract Despite advances in many domains, the field of solid organ transplantation remains limited by two distinct but connected problems: (1) a critical shortage of donor organs and (2) suboptimal graft longevity due to chronic alloimmune-mediated injury. For patients with end-stage renal disease, these limitations are readily apparent, with over 90,000 individuals in the United States awaiting kidney transplantation. This severe shortfall of donor kidneys is compounded by the suboptimal longevity of transplanted allografts, with a median kidney graft survival of only 8-12 years despite advances in immunosuppression. These significant limitations indicate a clear unmet need to develop novel approaches to improve the function of donor kidneys and enhance graft longevity. The treatment of donor organs with gene therapies has long been recognized as a promising strategy to enhance graft function and diminish graft immunogenicity, but until recently there have not been feasible approaches for gene delivery in an organ-specific manner. Over the last decade, the clinical development of ex vivo organ perfusion systems has created an ideal platform for selectively delivering gene therapies directly to donor allografts. Advancing this approach toward clinical use requires testing in a non-human primate transplant model using clinically relevant immunosuppression regimens. For this proposal, we have assembled a team of investigators with expertise in ex vivo organ perfusion, the use of adeno-associated viral (AAV) vectors for gene therapy, immune management, and kidney transplantation. We have 3 specific aims: 1) Optimize ex vivo machine perfusion approaches for delivery of gene therapies to kidney grafts in an auto-transplant model, 2) Determine the impact of the alloimmune response on transgene expression in kidney allografts, and 3) Evolve novel AAV vectors with tropism for human kidney grafts. Successful completion of this project will demonstrate the use of genetic engineering approaches to achieve durable transgene expression in kidney grafts. This approach has the potential to establish a new paradigm of genetically augmented solid organ allografts and transform approaches in solid organ transplantation.

摘要