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

失明是一个日益严重的全球性问题，给患者和整个社会带来了社会经济影响。退行性视网膜疾病约占全球失明的26%，影响着欧盟约3400万人。基因疗法、光遗传工具、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，但这些都是仅适用于少数患者的高成本疗法。眼睛适合移植，所以只要有现成的细胞来源，更换功能失调的光感受器应该是可行的。在晚期视网膜变性的临床前期模型中，多能干细胞(PSCs)可以产生视锥和视杆感受器，这些感受器能够整合到宿主视网膜并挽救视力，但同种异体PSC来源的感光细胞的有效长期整合受到宿主免疫反应的阻碍。为了克服这一障碍并使大量的光感受器变性患者能够获得这种治疗方法，我建议：(1)产生现成的、免疫透明(低免疫原性)的PSC来源的光感受器；(2)评估它们在逃避宿主免疫系统方面的有效性；(3)在晚期视网膜变性的临床前模型中确定它们的长期整合和恢复视力的能力。这一新的高增益方法提供了一个改变游戏规则、有效和可扩展的光感受器移植平台，以及一个亟需的范式转变，将改善数百万失明视网膜疾病患者的生活质量。通过参与成功的通过角膜缘干细胞移植逆转角膜失明的I/II期临床试验，我有一个独特的机会将我的研究成果转化为对这种罕见疾病患者的治疗。我现在的目标是建立和验证一个新的细胞移植平台，它将彻底改变视网膜变性的治疗方法。

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.