Interphotoreceptor Matrix Based Cell Delivery Vehicle for Retinal Regeneration

用于视网膜再生的基于光感受器间基质的细胞递送载体

• 批准号: 8032073
• 负责人: Rebecca L Carrier
• 金额: $ 23万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8032073
• 关键词: Adult; Age; Age related macular degeneration; Area; Biochemical; Biocompatible Materials; Biomimetics; Cattle; Cell Death; Cell Survival; Cell-Matrix Junction; Cells; Cessation of life; Chemical Engineering; Chemistry; Chondroitin Sulfate Proteoglycan; Chondroitinases; Clinical Treatment; Cues; Degenerative Disorder; Dependence; Development; Disease; Electron Microscopy; Ensure; Environment; Excision; Eye; Family suidae; Hyaluronidase; Image; Immunohistochemistry; Implant; In Vitro; Knowledge; Label; Lectin; Macular degeneration; Modeling; Mus; Nerve; Nerve Regeneration; Patients; Phase; Photoreceptors; Polymers; Procedures; Process; Research; Residual state; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Retinopathy of Prematurity; Screening procedure; Stem cells; Structure; Structure of retinal pigment epithelium; System; Techniques; Technology; Testing; Tissue Engineering; Tissues; Vertebrate Photoreceptors; Vision; Work; base; biomaterial development; cell motility; cell type; clinically relevant; design; experience; fetal; implantation; improved; in vitro testing; in vivo; jacalin; lentil lectin; meetings; nanoscale; nerve stem cell; novel; novel therapeutics; response; restoration; retinal progenitor cell; retinal regeneration; retinal rods; scaffold; stem; stem cell differentiation; success

DESCRIPTION (provided by applicant): In this project, natural matrix-based cell delivery vehicles for retinal progenitor cell (RPC) delivery to the subretinal space will be developed and tested, providing a novel therapeutic strategy for retinal regeneration. Specifically, interphotoreceptor matrix (IPM), the specialized matrix that surrounds the outer segments of rod and cone photoreceptors and occupies the space between the photoreceptors and retinal pigment epithelium, will be used as a base material for cell delivery vehicles. The developmental age of the IPM and removal of molecules inhibitory to neural regeneration (chondroitin sulfate proteoglycans) will be explored as key factors in creating an environment promoting seeded cell migration, integration into host retina, and differentiation. Implantation of RPCs into the subretinal space has recently shown tremendous promise as a therapy capable of restoring visual function. However, major barriers to the success of this therapy include extremely low levels (<1%) of cell integration into host retina and high levels of implanted cell death. A promising approach has been the use of synthetic polymers as scaffolds for cell-polymer composites which are implanted; these materials have resulted in 16-fold enhancement in cell survival, but levels are still inhibitively low. It is hypothesized that precise structural and biochemical cues provided by native IPM will promote integration of seeded RPCs into host retina, retinal regeneration, and restoration of visual function. The cell delivery vehicles developed in this project could provide a feasible clinical treatment for retinal degeneration associated with a wide variety of diseases, including macular degeneration and retinopathy of prematurity. The specific aims of the project, designed to test the central hypothesis, include developing and biochemically/ structurally characterizing IPM based cell delivery vehicles, testing in vitro cellular response to developed vehicles, and testing ability to promote retinal regeneration and visual function in vivo. In the first specific aim, procedures for isolating, processing, and characterizing IPM vehicles will be developed. IPM will be isolated from adult and fetal porcine eyes, processed to remove residual cellular material, treated for removal of chondroitin sulfate proteoglycans, and characterized structurally and biochemically. In the second aim, RPCs will be seeded onto IPM vehicles and cultured in a retinal explants model. The attachment, proliferation, alignment, expression of photoreceptor-specific markers, and integration into cultured retina will be studied. Finally, in aim 3, promising IPM based vehicles will be seeded with RPCs and implanted into the subretinal space of mice. Cell survival, differentiation, integration into host retina, and ability to promote retinal regeneration and visual function will be assessed. The research team has the interdisciplinary expertise essential to ensure success in meeting the overall objective, including a chemical engineer with expertise in biomaterial development, a neuroscientist with extensive experience in cell-polymer retinal regeneration strategies, and a neuroscientist with expertise in neural regeneration and stem/progenitor cells. PUBLIC HEALTH RELEVANCE: This project will result in development of a novel, natural matrix-based cell delivery vehicle for delivery of retinal progenitor cells (RPCs) to the subretinal space to promote retinal regeneration and restoration of visual function in patients suffering from retinopathies including macular degeneration and retinopathy of prematurity. While the strategy of progenitor cell delivery to the subretinal space has demonstrated hugely promising results, including some vision rescue, major barriers to success are low levels of RPC integration (<1%) into host retina and high levels of RPC death. Here, the natural structural and biochemical cues provided by native interphotoreceptor matrix (IPM) will be used to promote RPC survival and integration into adjacent host retina.

描述（由申请人提供）：在本项目中，将开发和测试用于视网膜祖细胞（RPC）递送到视网膜下空间的天然基质细胞递送载体，为视网膜再生提供一种新的治疗策略。具体来说，光感受器间基质（interphotoreceptor matrix， IPM），一种围绕杆状和锥状光感受器外段并占据光感受器和视网膜色素上皮之间空间的特殊基质，将被用作细胞递送载体的基础材料。IPM的发育年龄和抑制神经再生的分子（硫酸软骨素蛋白多糖）的去除将被视为创造促进种子细胞迁移、整合到宿主视网膜和分化的环境的关键因素。在视网膜下空间植入RPCs作为一种能够恢复视觉功能的治疗方法，最近显示出巨大的希望。然而，这种疗法成功的主要障碍包括极低水平（<1%）的细胞融入宿主视网膜和高水平的植入细胞死亡。一种很有前途的方法是使用合成聚合物作为植入细胞-聚合物复合材料的支架；这些材料使细胞存活率提高了16倍，但抑制水平仍然很低。据推测，天然IPM提供的精确的结构和生化线索将促进种子RPCs融入宿主视网膜，视网膜再生和视觉功能恢复。本项目开发的细胞递送载体可为包括黄斑变性和早产儿视网膜病变在内的多种疾病相关的视网膜变性提供可行的临床治疗。该项目的具体目标是测试中心假设，包括开发和生物化学/结构表征基于IPM的细胞递送载体，测试体外细胞对开发载体的反应，以及测试促进视网膜再生和体内视觉功能的能力。在第一个具体目标中，将开发隔离、处理和表征IPM车辆的程序。IPM将从成年和胎儿猪眼中分离，处理以去除残留的细胞物质，处理以去除硫酸软骨素蛋白聚糖，并进行结构和生化表征。在第二个目标中，RPCs将被播种到IPM载体上，并在视网膜外植体模型中培养。将研究光感受器特异性标记物的附着、增殖、排列、表达以及在培养视网膜中的整合。最后，在目标3中，有希望的基于IPM的载体将植入rpc并植入小鼠的视网膜下空间。将评估细胞存活、分化、融入宿主视网膜以及促进视网膜再生和视觉功能的能力。研究团队拥有确保成功实现总体目标所必需的跨学科专业知识，包括具有生物材料开发专业知识的化学工程师，具有细胞-聚合物视网膜再生策略丰富经验的神经科学家，以及具有神经再生和干细胞/祖细胞专业知识的神经科学家。