Regenerative Therapy for Corneal Endothelial Dystrophies and Injuries

角膜内皮营养不良和损伤的再生治疗

• 批准号: 9910087
• 负责人: HIRANMOY DAS
• 金额: $ 30万
• 依托单位: RASHMIVU, LLC
• 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 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910087
• 关键词: Address; Animals; Back; Blindness; Burn injury; Businesses; Capital; Cell Density; Cell Survival; Cells; Clinical Trials; Cornea; Corneal Endothelium; Country; Cyclic GMP; Data; Development; Disease; Dose; Effectiveness; Endothelial Cells; Endothelium; Engraftment; Exclusion Criteria; Eye; Formulation; Freezing; Funding; Goals; Grant; Health Care Costs; Human; Immune response; Individual; Injections; Injury; Investments; Keratoplasty; Lead; Letters; Methods; Modeling; Mus; Operative Surgical Procedures; Ophthalmologist; Ophthalmology; Oryctolagus cuniculus; Outpatients; Paint; Pathway interactions; Patients; Pharmacologic Substance; Phase; Phenotype; Privatization; Procedures; Recovery; Regulatory Affairs; Safety; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Societies; Source; Surgeon; Suspensions; Talents; Technology; Thick; Time; Tissue Procurements; Toxic effect; Transplantation; Trauma; Tumorigenicity; Vendor; anterior chamber; base; commercialization; cost; dosage; endothelial stem cell; healing; meetings; member; migration; monolayer; phenotypic biomarker; pre-clinical; preclinical study; preclinical trial; programs; public health relevance; regenerative; regenerative therapy; research and development; response; stem cell therapy; stem cells; targeted delivery; treatment optimization; tumor

Summary Worldwide, only 1 out of 70 patients with corneal endothelial dystrophies and injuries receive a corneal transplant due to the limited corneal donor pool, the need for advanced surgical facilities and talent, and expense. RashmiVu is developing a stem cell based regenerative technology that addresses this large unmet global need through a paradigm shift, wherein treatment could be as simple as an intracameral injection of stem cells as an outpatient procedure. RashmiVu has repeatedly demonstrated successful isolation and expansion of human corneal endothelial stem cells (hCESCs) into millions, confirmed that these cells are hCESCs by analysis of phenotypic markers, and demonstrated their regenerative potential in preliminary animal studies in both mice and rabbits. This Fast-Track STTR seeks to complete development and demonstrate potential products including (a) a single cell suspension for intracameral injection, (b) a single cell formulation that can be “painted” onto the corneal endothelium, and (c & d) sheets of hCESCs and/or their differentiated mature corneal endothelial phenotypes for use in DSEK and DMEK surgeries. Phase I Specific Aims: 1. Cell Yield: Determine tissue procurement inclusion/exclusion criteria that reliably yield 5M+ hCESCs/donor eye, and optimize differentiation to maximize yield of mature CEC phenotypes; 2. Definitive healing: Rapid innate healing in rabbits obfuscates effects of hCESCs (see Prelim Data). The team will complete development of a slow-healing cryoinjury rabbit model and demonstrate definitive hCESC efficacy; 3. Mechanisms: Determine mechanisms potentiated by or convertible to a pharmaceutical pathway. Phase II Specific Aims: 4. Cell suspension formulations: Optimize cell suspensions for injection and targeted delivery including ROCKi pre-treatment, and optimize media and methods for high cell survival after freezing, storage, thawing, and revival; 5. Cell Sheets: Develop monolayer sheets of hCESCs on transplantable substrates, develop a method for consistent differentiation of the hCESC monolayer into a mature CEC monolayer on these sheets, and demonstrate successful partial thickness transplantation (DSEK) in rabbits; 6. Dosage, Safety & Efficacy: Initiate FDA-recommended pre-clinical trials to demonstrate safety, efficacy, effectiveness of targeted delivery approaches including dose response, cell survival, engraftment, distribution, migration, proliferation, tumorigenicity, host immune response, and cellular toxicities. A successful regenerative treatment for corneal endothelial dystrophies and damages could dramatically reduce health care costs, eliminate blindness, and return people to fully functioning members of society, all with an attractive market opportunity.

概括 在全球范围内，在70名角膜内皮营养不良和受伤的患者中，只有1例接受角膜 由于角膜供体池有限，需要先进的手术设施和人才以及 费用。 Rashmivu正在开发一种基于干细胞的再生技术，该技术解决了这一大型未定的 通过范式转移的全球需求，其中治疗可能像室内注入一样简单 干细胞作为门诊手术。 Rashmivu反复证明了成功的隔离和 将人角膜内皮干细胞（HCESC）扩展到数百万，证实这些细胞是 通过对表型标记的分析HCESC，并证明了它们在初步的再生潜力 小鼠和兔子的动物研究。这款快速轨道的STTR试图完成开发和 展示潜在的产品，包括（a）用于腔内注射的单细胞悬浮液，（b）单个细胞 可以“涂上”到角膜内皮的地层，以及（C＆D）HCESC和/或它们的床单 分化的成熟角膜内皮表型用于DSEK和DMEK手术。 第一阶段特定目的：1。细胞产量：确定可靠性的组织采购包含/排除标准 产量为5M+ HCESC/供体眼，并优化分化以最大程度地提高成熟CEC表型的产量； 2。 确定的愈合：兔子中的快速先天治疗混淆了HCESC的影响（请参阅Prelim Data）。团队 将完成缓慢治疗的冷冻兔模型的开发，并展示确定的HCESC 效率; 3.机制：确定可能通过或可转换为药物途径的机制。 II期特异性目的：4。细胞悬架公式：优化注射细胞悬浮液并靶向 交付包括Rocki预处理，并优化冰冻后高细胞存活的培养基和方法， 存储，解冻和复兴； 5。细胞表：在可移植上开发HCESC的单层板 底物，开发一种将HCESC单层一致分化为成熟CEC的方法 这些床单上的单层，并在兔子中表现出成功的部分厚度移植（DSEK）； 6。 剂量，安全性和功效：启动FDA征用的临床前试验，以证明安全性，效率， 有针对性输送方法的有效性，包括剂量反应，细胞存活，植入，分布， 迁移，增殖，肿瘤性，宿主免疫响应和细胞毒性。 对于角膜内皮营养不良和损害的成功再生治疗可能是巨大的 降低医疗保健成本，消除失明，并将人们返回社会的功能齐全的成员 有吸引力的市场机会。