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 摘要 角膜失明是导致全球失明的主要原因，其中同种异体角膜移植(CT)是 全球最常见的组织移植形式。尽管进行了大约18万例CT手术 目前，每年约有1270万人在等待捐赠者的角膜进行手术。尽管如此，CT 手术伴随着很高的失败率：多达20%-30%的角膜移植物在第一次手术中被拒绝 在普通人群和占人口20%以上的高危病例中，几乎所有 移植物在3年内被拒绝。CT失败给本已有限的供体角膜供应带来了压力， 大约每需要70个眼角膜，就有一个眼角膜。无论是由于无法访问还是由于 干预不成功，绝大多数角膜失明病例得不到治疗，留下患者 行动不便，跌倒的风险增加，情绪困扰，死亡率增加。当前的方法 为了减轻角膜移植排斥反应，涉及局部和全身皮质类固醇和免疫抑制剂， 但这些方法都有严重的缺点；已知皮质类固醇可以诱导视力。 损失和免疫抑制剂，除了会招致严重的潜在副作用外，还会带来高昂的价格。 解决减少移植物失败和提高长期成功的方法的迫切需要 同种异体人类CT，Bedock Treateutics建议使用腺相关病毒(AAV)介导 转导人类白细胞抗原G亚型到供体角膜移植物以最终调节免疫学 人类受者的反应和CT后的排斥反应。这份第一阶段提案的重点是前 影响角膜植体AAV载体转导的已识别变量的活体优化。治疗 有效性和可行性将通过追求两个具体目标来实现：1)优化AAV-HLA- Gcomo体外转导变量(即载体产量、剂量和孵化时间)，以及2)评估 AAV-HLA-Gcomo在高危兔同种异体CT模型中的体外转导效果。基岩治疗公司 以往的研究已经证明了利用AAV8G9转导人类白细胞抗原G亚型进入供体的可行性 在同种异体CT动物模型中成功预防移植排斥反应。 移植前将人类白细胞抗原-G导入兔角膜可完全预防 对照组角膜移植排斥反应持续时间为80天，对照组为10天。成功 该方法的应用为获得免疫耐受的角膜提供了平台，解决了免疫耐受角膜的高产率问题 角膜移植排斥反应和改善目前的组织短缺问题。完成拟议的工作 将为其他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 人类CT，以改善数千名经历角膜排斥反应的患者的生活质量 每年。 项目摘要/摘要第6页