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

描述(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主要公共健康负担。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。目前还没有有效的治疗方法。我们最近的研究表明，在视网膜变性的啮齿动物模型中，在变性的早期一次静脉注射骨髓间充质干细胞(MSCs)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。我们建议在视网膜变性的啮齿动物模型中使用非侵入性干细胞疗法来开发一种保护视力和限制血管病理的治疗方案。我们推测，全身应用MSCs治疗正在进行的视网膜变性将减缓光感受器丢失的进程，并通过促进旁分泌和自分泌介质的释放来稳定/修复继发性血管病变。提出了以下具体目标：(1)确定MSC在RCS大鼠变性早期的剂量反应和长期安全性和有效性；(2)研究MSC在RCS大鼠和ELOVL4小鼠变性后期的神经血管保护作用；(3)检测MSC归巢到视网膜的分子机制和静脉给药后的有效性。根据目前使用MSCs作为再生医学和退化医学治疗的广泛临床经验，如果在动物模型中获得积极结果，这种治疗方法有可能移植到临床上。 公共卫生意义：视网膜变性和相关的眼血管病变是美国不可逆性失明的主要病程，目前还没有有效的治疗方法。我们建议在视网膜变性的啮齿动物模型中，通过系统注射多能骨髓来源干细胞(MSCs)来发展基于细胞的非侵入性治疗来保护视力和限制病理性血管改变。骨髓间充质干细胞作为自体细胞在临床挽救视力、稳定/修复眼部血管病变方面具有很大的潜力。

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.