Development of non-invasive cell-based therapy for retinal degeneration and assoc

开发针对视网膜变性及其相关的非侵入性细胞疗法

• 批准号: 8308102
• 负责人: Shaomei Wang
• 金额: $ 35.32万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308102
• 关键词: Affect; Age related macular degeneration; Allogenic; Animal Model; Area; Autologous; Blindness; Blood Vessels; Bone Marrow; CXCR4 gene; Cell Adhesion Molecules; Cell Survival; Cell Therapy; Cells; Cessation of life; Clinic; Clinical; Defect; Development; Disease; Dose; Encapsulated; Extravasation; Eye; Eye Development; Eye diseases; Growth Factor; Homing; Injection of therapeutic agent; Mediator of activation protein; Medicine; Mesenchymal Stem Cells; Modeling; Modification; Molecular; Mus; Neurodegenerative Disorders; Pathology; Photoreceptors; Play; Public Health; Rattus; Research; Retina; Retinal; Retinal Degeneration; Retinitis Pigmentosa; Rodent Model; Role; Safety; Social Impacts; Staging; Stem cells; Stromal Cell-Derived Factor 1; Structure of retinal pigment epithelium; Study models; Surgeon; Testing; Therapeutic Effect; Time; Translations; Treatment Protocols; United States; Up-Regulation; Vision; autocrine; base; chemokine; college; economic impact; effective therapy; experience; implantation; inherited retinal degeneration; intravenous administration; intravenous injection; paracrine; photoreceptor degeneration; programs; protective effect; public health relevance; regenerative; release factor; repaired; response; stem cell therapy; subretinal injection

DESCRIPTION (provided by applicant): Retinal degeneration and related diseases are the leading cause of blindness and represent a major public health burden with economical and social impacts. As photoreceptor loss, the development of secondary vascular pathology causes disastrous consequences for vision. There is no effective treatment available. Our recent study revealed that a single intravenous injection of bone marrow derived mesenchymal stem cells (MSCs) at early stages of degeneration can preserve photoreceptors from death, sustain visual function, and limit pathological vascular changes in a rodent model of retinal degeneration. We propose to develop a treatment protocol that preserves vision and limits vascular pathology using non-invasive stem cell therapy in rodent models for retinal degeneration. We hypothesize that systemic administration of MSCs to treat ongoing retinal degeneration will slow the progress of photoreceptor loss and stabilize/repair the secondary vascular pathology by promoting the release of paracrine and autocrine mediators. The following specific aims are proposed: (1) Determine dose-response and long-term safety and efficacy of MSC treatment at early stages of degeneration in the RCS rat; (2) Investigate the neuro-vascular protective effects of MSCs at later stages of degeneration in the RCS rat and in Elovl4 mouse; (3) Examine the molecular mechanism of MSC homing to the retina and efficacy after intravenous administration. Based on the current extensive clinical experience using MSCs as therapy for both regenerative and degenerative medicine, if positive results are obtained in animal models, this treatment has a realistic likelihood of translation to the clinic. PUBLIC HEALTH RELEVANCE: Retinal degeneration and associated ocular vascular pathology are the leading course of irreversible blindness in the USA, there is no effective treatment yet. We propose to develop non-invasive cell-based therapy to preserve vision and limit the pathological vascular modification by systemic administration of multipotent bone marrow derived stem cells (MSCs) in rodent models for retinal degeneration. The MSCs have great potential for clinic as autologous cells to rescue vision and stabilize/repair ocular vascular pathology.

描述（由申请人提供）：视网膜变性和相关疾病是导致失明的主要原因，是具有经济和社会影响的重大公共卫生负担。随着光感受器的丧失，继发性血管病变的发展会对视力造成灾难性的后果。目前尚无有效的治疗方法。我们最近的研究表明，在视网膜变性的啮齿动物模型中，在变性的早期阶段单次静脉注射骨髓来源的间充质干细胞（MSC）可以保护光感受器免于死亡，维持视觉功能并限制病理性血管变化。我们建议开发一种治疗方案，在啮齿动物视网膜变性模型中使用非侵入性干细胞疗法来保留视力并限制血管病理。我们假设全身施用间充质干细胞来治疗正在进行的视网膜变性将减缓光感受器损失的进展，并通过促进旁分泌和自分泌介质的释放来稳定/修复继发性血管病理。提出以下具体目标：（1）确定RCS大鼠变性早期阶段MSC治疗的剂量反应以及长期安全性和有效性； (2) 研究RCS大鼠和Elovl4小鼠变性后期MSCs的神经血管保护作用； (3)考察MSC归巢视网膜的分子机制及静脉给药后的功效。根据目前使用间充质干细胞作为再生和退行性疾病治疗的广泛临床经验，如果在动物模型中获得积极结果，这种治疗就有可能转化为临床。 公共卫生相关性：视网膜变性和相关的眼部血管病变是美国不可逆失明的主要原因，目前尚无有效的治疗方法。我们建议开发非侵入性细胞疗法，通过在啮齿动物视网膜变性模型中全身施用多能骨髓干细胞（MSC）来保留视力并限制病理性血管改变。间充质干细胞作为自体细胞在临床上具有挽救视力和稳定/修复眼部血管病理的巨大潜力。