Prevention of corneal transplant rejection using AAV-HLA-G combination therapy

使用 AAV-HLA-G 联合疗法预防角膜移植排斥反应

基本信息

批准号：
10354308
负责人：
BRIAN C GILGER
金额：
$ 17.19万
依托单位：
BEDROCK THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2021-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10354308
关键词：
Accounting Acute Address Adrenal Cortex Hormones Affect Allogenic Animal Model Antigens Blindness Capsid Clinical Research Combined Modality Therapy Cornea Corneal Diseases Cytotoxic T-Lymphocytes DNA cassette Dependovirus Disadvantaged Dose Engineering Engraftment Ensure Evaluation Failure General Population Goals Graft Rejection Graft Tolerance HLA G antigen Health Care Costs Human Immune Immune Tolerance Immune response Immunosuppressive Agents Intervention Isomerism Keratoplasty Mediating Methods Modeling Operative Surgical Procedures Oryctolagus cuniculus Outcome Patient-Focused Outcomes Patients Phase Population Preparation Prevention Price Production Productivity Prognosis Protein Isoforms Proteins Quality of life RNA Splicing Symptoms Testing Therapeutic Time Tissue Transplantation Tissues Transplantation Transplantation Surgery Treatment Efficacy Up-Regulation Vascularization Work adeno-associated viral vector base economic impact emotional distress experience experimental study fall risk graft failure high risk immunomodulatory therapies immunoregulation improved mortality operation preclinical study prevent side effect success therapy development transplant model vector

项目摘要

Contact PD/PI: GILGER, BRIAN C Abstract Corneal blindness is a leading cause of global blindness, with allogeneic corneal transplantation (CT) being the most common form of tissue transplantation worldwide. Though approximately 180,000 CT surgeries are carried out each year, around 12.7 million are currently awaiting a donor cornea to undergo the operation. Still, CT surgery is accompanied by a high failure rate: as many as 20–30% of corneal grafts are rejected within the first 5 years in the general population, and in high-risk cases, which represent over 20% of the population, almost all grafts are rejected within 3 years. CT failure puts a strain on the already-limited supply of donor corneas, for which there is approximately only one cornea available for every 70 needed. Whether by lack of access or unsuccessful intervention, the vast majority of cases of corneal blindness go untreated, leaving patients with limited mobility, an increased risk of falls, emotional distress, and an increase in mortality. Current approaches to mitigate corneal graft rejection involve topical and systemic corticosteroids and immunosuppressive agents, but these methods are all burdened with acute disadvantages; corticosteroids have been known to induce vision loss, and immunosuppressive agents, besides incurring serious potential side effects, also come at a high price. To address the critical need for methods to reduce graft failure and improve the long-term success of allogeneic human CT, Bedrock Therapeutics proposes to use adeno-associated virus (AAV)-mediated transduction to deliver HLA-G isoforms to donor corneal grafts to ultimately modulate the immunologic response of a human recipient and prevent rejection following CT. This Phase I proposal focuses on the ex vivo optimization of identified variables that affect AAV vector transduction of corneal explants. Treatment efficacy and feasibility will be targeted through the pursuit of two specific aims: 1) optimization of AAV-HLA- Gcombo ex vivo transduction variables (i.e., vector production, dose, and incubation time), and 2) evaluation of AAV-HLA-Gcombo ex vivo transduction efficacy in a high-risk rabbit allogenic CT model. Bedrock Therapeutics' previous studies have demonstrated the feasibility of using AAV8G9 to transduce HLA-G isoforms into donor corneas and the resulting successful prevention of graft rejection in animal models of allogeneic CT. Transduction of HLA-G into rabbit corneas prior to transplantation resulted in complete prevention of allogeneic graft rejection over an 80-day period vs. rejection at 10 days in control corneas. Successful application of this method will provide a platform for obtaining immune-tolerant corneas, addressing the high rate of corneal graft rejection and ameliorating current tissue shortage problems. Completion of the proposed work will pave the way for additional preclinical and clinical studies with an eventual goal of applying our platform to human CT in order to improve the quality of life of the thousands of patients that experience corneal rejection each year. Project Summary/Abstract Page 6

联系人 PD/PI：GILGER、BRIAN C 抽象的角膜失明是全球性失明的主要原因，同种异体角膜移植（CT）是解决这一问题的重要手段。世界范围内最常见的组织移植形式，但已进行了约 180,000 例 CT 手术。目前，每年约有 1270 万人正在等待捐赠角膜进行手术。手术失败率很高：多达 20-30% 的角膜移植物在第一次移植后被排斥普通人群中 5 年，以及占人口 20% 以上的高危病例中，几乎所有移植物在 3 年内被拒绝，给本已有限的供体角膜供应带来了压力。无论是由于缺乏通道还是由于缺乏通道，大约每 70 个人就只有一个可用的角膜。如果干预不成功，绝大多数角膜失明病例都得不到治疗，导致患者行动受限、跌倒风险增加、情绪困扰以及死亡率增加。减轻角膜移植排斥涉及局部和全身皮质类固醇和免疫抑制剂，但这些方法都存在明显的缺点；众所周知，皮质类固醇会诱发视力。免疫抑制剂除了会产生严重的潜在副作用外，价格也很高。满足对减少移植失败和提高移植长期成功率的迫切需求同种异体人类CT，Bedrock Therapeutics建议使用腺相关病毒（AAV）介导转导将 HLA-G 亚型递送至供体角膜移植物，最终调节免疫学人类接受者的反应并防止 CT 后的排斥反应这一阶段的提案重点关注前任。影响角膜外植体 AAV 载体转导的已确定变量的体内优化。将通过追求两个具体目标来确定功效和可行性：1）AAV-HLA-的优化 Gcombo 离体转导变量（即载体产生、剂量和孵育时间），以及 2) 评估 AAV-HLA-Gcombo 在高风险兔同种异体 CT 模型中的体外转导效果。之前的研究已经证明了使用 AAV8G9 将 HLA-G 亚型转导为供体的可行性角膜以及由此在同种异体 CT 动物模型中成功预防移植排斥。在移植前将 HLA-G 转入兔角膜可完全预防 80 天的同种异体移植排斥与对照角膜 10 天的排斥。该方法的应用将为获得免疫耐受的角膜提供一个平台，解决高比率的问题角膜移植排斥反应和改善当前的组织短缺问题完成拟议的工作。将为更多的临床前和临床研究铺平道路，最终目标是将我们的平台应用于人体 CT 旨在改善数千名经历角膜排斥反应的患者的生活质量每年。项目总结/摘要第 6 页