Off-the-shelf hypoimmunogenic photoreceptors for treatment of blinding retinal disease

现成的低免疫原性光感受器用于治疗致盲性视网膜疾病

• 批准号: EP/Y031016/1
• 负责人: Majlinda Lako
• 金额: $ 269.72万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY031016%2F1
• 关键词: Off; shelf; hypoimmunogenic; photoreceptors; treatment

Blindness represents an increasing global problem with socio-economic impacts for the patients and society in general. Degenerative retinal diseases account for approximately 26% of global blindness affecting ~ 34 million people in the EU. Gene therapy, optogenetic tools, photosensitive switches and retinal prostheses have shown promising outcomes for restoring vision, but these are high-cost therapies applicable only to a small number of patients. The eye is suitable for transplantation so replacing dysfunctional photoreceptors should be feasible as long as sources of such cells are readily available. Pluripotent stem cells (PSCs) can generate cone and rod photoreceptors, which are able to integrate into the host retina and rescue vision in pre-clinical models of advanced retinal degeneration, but efficient long-term integration of allogeneic PSC-derived photoreceptors is impeded by the host immune response. To overcome this barrier and make this treatment accessible to a large number of patients with photoreceptor degeneration, I propose to: (1) generate off-the-shelf, immune-transparent (hypoimmunogenic) PSC-derived photoreceptors; (2) assess their effectiveness in evading the host immune system and (3) determine their long-term integration and ability to restore vision in pre-clinical models of advanced retinal degeneration. This novel high-gain approach provides a game-changing, effective and scalable photoreceptor transplantation platform, and a much-needed paradigm shift that will improve the quality of life for the millions of sufferers with blinding retinal disease. Through my involvement in successful phase I/II clinical trials of reversing corneal blindness via transplantation of limbal stem cells, I have had a unique opportunity to translate my research findings into treatments for patients with this rare disease. I now aim to build and validate a novel cell transplantation platform that will revolutionise the treatment of retinal degeneration.

失明是一个日益严重的全球性问题，对患者和整个社会都有社会经济影响。退行性视网膜疾病约占全球失明的 26%，影响了欧盟约 3400 万人。基因疗法、光遗传学工具、光敏开关和视网膜假体在恢复视力方面显示出有希望的结果，但这些疗法成本高昂，仅适用于少数患者。眼睛适合移植，因此只要有容易获得此类细胞的来源，替换功能障碍的光感受器就应该是可行的。多能干细胞（PSC）可以产生视锥细胞和视杆细胞感光细胞，这些细胞能够整合到宿主视网膜中并在晚期视网膜变性的临床前模型中挽救视力，但同种异体 PSC 衍生的感光细胞的有效长期整合受到以下因素的阻碍：宿主的免疫反应。为了克服这一障碍并使大量光感受器变性患者能够接受这种治疗，我建议：（1）生成现成的、免疫透明（免疫原性低）的 PSC 衍生光感受器； （2）评估它们逃避宿主免疫系统的有效性，（3）确定它们在晚期视网膜变性临床前模型中的长期整合和恢复视力的能力。这种新颖的高增益方法提供了一个改变游戏规则的、有效的和可扩展的光感受器移植平台，以及急需的范式转变，这将改善数百万患有致盲性视网膜疾病的患者的生活质量。通过参与通过角膜缘干细胞移植逆转角膜失明的成功的 I/II 期临床试验，我获得了一个独特的机会，可以将我的研究成果转化为治疗这种罕见疾病的患者。我现在的目标是建立并验证一个新颖的细胞移植平台，该平台将彻底改变视网膜变性的治疗。