Retinitis pigmentosa therapy with human embryonic stem cell- and induced pluripotent stem cell-derived photoreceptor progenitors

 描述(申请人提供)：高级细胞技术公司(ACT)是一家临床阶段的生物技术公司，专注于再生医学和细胞治疗技术的开发和商业化。该公司最先进的产品正在进行开创性的临床试验，用于治疗各种与眼睛相关的衰弱疾病。这项SBIR第一阶段应用的总体目标是扩展先前的研究，并提供概念证明，即人多能干细胞(PSC)来源的光感受器前体细胞(PSC-PhRPs)能够通过移植来自人类胚胎干细胞(HESCs)的PhRPs和使用大鼠诱导的多潜能干细胞(IPSCs)来防止视网膜色素变性(RP)的进展。研究将确定这些移植的PSC-PhRPs是否会促进宿主光感受器的存活并分化为成熟的光感受器，维持视网膜连接，保护视力，并使基于PHRP细胞的RP治疗方法的进一步发展合理化。视网膜退行性疾病，如RP、老年性黄斑变性和视杆/视杆细胞营养不良，其特征是感光细胞丢失，导致永久性失明和常常失明；目前没有 根治疗法是存在的。这些情况对生活质量、生产力和医疗费用造成了广泛的社会负担，因此迫切需要开发视网膜存活、修复和替换的策略，以对抗RP和其他视网膜退行性疾病。最近的动物研究表明，光感受器细胞置换是治疗视网膜变性的一种有前景的治疗策略，尽管细胞整合和视觉功能的恢复尚未实现。阻碍该领域进展的因素包括捐献细胞的供应有限和细胞纯度有问题。为了克服这些障碍，ACT开发了一种独特的方法，以多种hESC和IPSC系为起始材料，将人PSC分化为纯的、可再生的视网膜光感受器细胞群。初步研究表明，这些PSC-PhRPs在体外能够进一步分化，形成表达视紫红质和视蛋白的成熟光感受器，当移植到RCS大鼠的玻璃体中时，分化为表达视紫红质和恢复素的成熟视杆感受器。对终末期视网膜变性小鼠的其他初步研究表明，PSC-PhRPs迁移并整合到外核层，在改善视动力反应方面具有治疗活性。在这项提案中，这些有希望的研究将扩展到确定当ACT的人PSC-PhRPs移植到RP大鼠的视网膜是否能够在疾病早期保护和挽救光感受器以限制退化的进展，以及它们是否也能够在疾病晚期取代退化的光感受器以恢复视觉功能。如果成功，启用IND的研究将在最终临床试验的第二阶段计划中启动。

 DESCRIPTION (provided by applicant): Advanced Cell Technology, Inc., (ACT) is a clinical stage biotechnology company focused on the development and commercialization of regenerative medicine and cell therapy technology. The company's most advanced products are in pioneering clinical trials for the treatment of a variety of eye-related debilitating diseases. he overall objective of this SBIR Phase I application is to extend previous studies and provide proof-of-concept that human pluripotent stem cell (PSC)-derived photoreceptor progenitors (PSC-PhRPs) are able to prevent progression of retinitis pigmentosa (RP) by transplantation of PhRPs derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) using a rat model of RP. Investigations will determine whether these grafted PSC-PhRPs will promote survival of host photoreceptors and differentiate into mature photoreceptors, maintain retinal connections, preserve vision, and rationalize further development of PhRP cell-based approaches for RP therapy. Retinal degenerative diseases such as RP, age-related macular degeneration, and rod/con dystrophies are characterized by loss of photoreceptor cells resulting in permanent loss of vision and often blindness; currently no curative therapy exists. These conditions exert extensive societal burdens on quality-of-life, productivity, and health- care costs, and thus an urgent need exists to develop strategies for retinal survival, repair, and replacement to combat RP and other degenerative diseases of the retina. Recent animal studies have shown that photoreceptor cell replacement is a promising therapeutic strategy for retinal degeneration, although robust cell integration and recovery of visual function has yet to be achieved. Impediments to progress in the field include a limited supply of donor cells and questionable cell purity. In order to overcome these barriers ACT has developed a unique method for robust differentiation of human PSCs into pure, renewable populations of retinal photoreceptor cells, successfully using multiple hESC and iPSC lines as starting material. In initial studies ACT has demonstrated that these PSC-PhRPs are able to further differentiate in vitro and form mature photoreceptors expressing rhodopsin and opsin and when transplanted into the vitreous of RCS rats differentiate into mature rod photoreceptors expressing rhodopsin and recoverin. Additional preliminary studies in end-stage retinal degenerated mice demonstrated that PSC-PhRPs migrated and integrated into the outer nuclear layer and were therapeutically active in improving optokinetic responses. In this proposal these promising studies will be extended to determine whether ACT's human PSC-PhRPs when grafted into retinas of RP rats are able to protect and rescue photoreceptors at an early stage of disease to limit progression of degeneration and whether they are also able to replace degenerated photoreceptors in late stage disease to restore visual function. If successful, IND-enabling studies will initiate in a Phase II program toward eventual clinical trial.