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

• 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
• 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

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PD/PI：Gilger，Brian C 抽象的 角膜失明是全球失明的主要原因，同种异体角膜移植（CT）是 全球组织移植的最常见形式。尽管进行了大约18万CT手术 每年，目前约有1,270万，目前正在等待捐赠者角膜进行操作。仍然，CT 手术是通过高衰竭率完成的：多达20-30％的角膜移植物在第一次被拒绝 一般人口5年，在高风险案件中，占人口的20％以上，几乎全部 移植物在3年内被拒绝。 CT失败给已经有限的供体角膜供应带来了压力，因为 每70个需要大约一个角膜。无论是由于缺乏访问还是 绝大多数角膜失明病例都没有治疗，使患者患有 流动性有限，跌倒风险增加，情绪困扰以及死亡率的增加。当前的方法 为了减轻角膜移植的拒绝涉及局部和全身性皮质类固醇以及免疫抑制剂， 但是这些方法都被急性灾难所燃烧。众所周知，皮质类固醇会引起视力 损失和免疫抑制剂除了产生严重的潜在副作用外，还以高价。 解决对减少移植失败并改善长期成功方法的关键需求 同种异体人CT，基岩治疗药物建议使用腺相关病毒（AAV）介导的 转导向供体角膜移植物输送HLA-G同工型以最终调节免疫学 人类接受者的反应并防止CT拒绝。我的建议重点是 影响角膜外植体AAV矢量翻译的已识别变量的体内优化。治疗 通过追求两个具体目的，将针对疗效和可行性：1）优化AAV-HLA- Gcombo Ex Vivo转导变量（即矢量产生，剂量和孵育时间），以及2）评估 高风险兔同种异体CT模型中的AAV-HLA-GCOMBO EX VIVO转移效率。基岩治疗学” 先前的研究表明，使用AAV8G9将HLA-G同工型转换为供体有可行性 角膜和由此产生的同种异体CT动物模型中成功预防移植排斥。 在移植之前将HLA-G转导向兔角膜，从而完全预防 在80天内的同种异体移植物拒绝与对照角膜的拒绝相比。成功的 这种方法的应用将为获得免疫耐受性角膜提供一个平台，以解决高率 角膜移植排斥和改善当前组织短缺问题。拟议工作的完成 将为其他临床前和临床研究铺平道路，最终将我们的平台应用于 人类CT，以提高成千上万经历角膜抑制的患者的生活质量 每年。 项目摘要/摘要页面6