Biomaterial enhancement of stem cell transplant efficacy for macular degeneration

生物材料增强干细胞移植治疗黄斑变性的功效

• 批准号: 8624438
• 负责人: Adah Almutairi
• 金额: $ 37.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624438
• 关键词: Address; Advanced Development; Affect; Age related macular degeneration; Animal Model; Area; Atrophic; Behavioral; Biochemistry; Biocompatible Materials; Biomaterials Research; Biopolymers; Blindness; Cell Differentiation process; Cell Transplants; Cells; Chemicals; Choroidal Neovascularization; Clinic; Collaborations; Commit; Derivation procedure; Drug Formulations; Elderly; Electroretinography; Ensure; Extracellular Matrix; Health; Hyaluronic Acid; Hydrogels; In Vitro; Injectable; Injection of therapeutic agent; Light; Macular degeneration; Mechanical Stress; Mechanics; Methods; Methylcellulose; Modeling; Modification; Patients; Pattern; Photoreceptors; Population; Positioning Attribute; Rattus; Recovery; Recovery of Function; Retina; Retinal; Rodent Model; Saline; Solutions; Stem cell transplant; Structure of retinal pigment epithelium; Surgeon; Survival Rate; Translations; Transplantation; Vision; Visual; Work; cell type; college; effective therapy; embryonic stem cell; geographic atrophy; human embryonic stem cell; in vivo; meetings; neurodevelopment; relating to nervous system; response; retinal neuron; retinal progenitor cell; stem cell differentiation; subretinal injection; success

Biomaterial enhancement of stem cell transplant efficacy for macular degeneration No effective therapies yet exist for advanced macular degeneration. Restoring vision in severe cases requires replacing both retinal pigmented epithelium (RPE) and photoreceptors because photoreceptors require functional RPE to survive. However, no approach to replace both cell types has yet been introduced. Further, previous attempts to replace photoreceptors have met limited success in rodent models, likely because of low survival rates and restricted distribution of transplanted cells. This project integrates solutions to both of these challenges: we propose to transplant human embryonic stem (ES) cell-derived primitive retinal stem cells (hpRSCs), a cell population that is more pluripotent than cell types previously transplanted to restore vision. We have shown that hpRSCs yield both RPE and photoreceptors in vitro and in vivo; replacing both cell types in vivo would yield longer-lasting visual improvements, as transplant-derived RPE would support transplant-derived photoreceptors. In order to develop a maximally effective therapy, we will deliver hpRSCs in an injectable hydrogel whose biochemistry and mechanics closely match those of the ocular extracellular matrix, which has recently been shown to uniformly distribute transplanted cells across the retina. This project stands to position ES cell-derived RPCs for translation into the clinic. The key to this advance is the collaboration between the PIs, bringing together a leader in macular degeneration models and the differentiation of stem cells into retinal neurons (Zhang) with a biomaterials research group (Almutairi). The Zhang group's expertise will ensure that this project advances development of HAMC for ocular transplantation significantly: previous work has not employed relevant animal models, so the impact of the material on transplanted cells' differentiation and functional recovery has not yet been assessed. Further, it has relied on cells that are easiest to derive, whereas this project will employ ES cell-derived RPCs, which are the only clinically viable option. By completion of this project, we expect to: 1. Assess the effect of HAMC delivery on survival and distribution of subretinally injected retinal stem cells 2. Define the effect of HAMC on the ability of retinal stem cells to differentiate into RPE and photoreceptors in vitro and in vivo 3. Identify the delivery method that maximizes visual improvement ensuing from subretinal injection of retinal stem cells in Royal College of Surgeons (RCS) rats

干细胞移植功效的生物材料增强黄斑变性 晚期黄斑变性尚无有效的疗法。在严重情况下恢复视力 需要替换视网膜色素上皮（RPE）和感光体，因为光感受器 需要功能性RPE才能生存。但是，尚无替换两种细胞类型的方法 引入。此外，以前替换感光器的尝试在啮齿动物中取得了有限的成功 模型，可能是由于存活率低和移植细胞分布的限制。 该项目将解决方案集成到这两个挑战：我们建议移植人类胚胎 茎（ES）细胞衍生的原始视网膜干细胞（HPRSC），这种细胞群比多能比 先前已移植以恢复视力的细胞类型。我们已经证明HPRSC同时产生RPE和 体外和体内的感光体；在体内替换两种细胞类型都会产生更长的视觉效果 改进，因为移植的RPE将支持移植衍生的光感受器。为了 开发最大有效的疗法，我们将在可注射的水凝胶中传递HPRSC，其水凝胶 生物化学和力学与眼细胞外基质的生物化学和力学紧密相匹配，该基质最近具有 被证明在整个视网膜上均匀地分布了移植的细胞。 该项目将ES衍生的RPC定位为转换为诊所。这一进步的关键 是PI之间的合作，将黄斑变性模型的领导者和 通过生物材料研究组（Almutairi），干细胞分化为视网膜神经元（Zhang）。这 张集团的专业知识将确保该项目为Ocular开发HAMC 移植显着：以前的工作尚未采用相关的动物模型，因此 尚未评估移植细胞分化和功能恢复的材料。更远， 它依赖于最容易得出的细胞，而该项目将采用ES衍生的RPC，即 这是唯一可行的临床选择。 通过完成该项目，我们希望： 1。评估HAMC递送对潜在注射的视网膜干细胞存活和分布的影响 2。定义HAMC对视网膜干细胞分化为RPE的能力的影响 体外和体内的感光体 3。确定从视网膜下注射后最大化视觉改进的交付方法 皇家外科医生学院（RCS）大鼠的视网膜干细胞