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

总结 视网膜变性和相关疾病是失明的主要原因， 造成经济和社会影响的健康负担。由于光感受器丧失， 血管病变对视力造成灾难性的后果。没有有效的治疗方法。我们 最近的一项研究表明，单次静脉注射骨髓间充质干细胞， 在退化的早期阶段，骨髓间充质干细胞（MSC）可以保护光感受器免于死亡，维持视觉功能， 限制视网膜变性啮齿动物模型中的病理性血管变化。我们建议发展一个 使用非侵入性干细胞疗法保护视力并限制血管病变的治疗方案， 视网膜变性的啮齿动物模型。我们假设全身给予间充质干细胞治疗持续性骨髓炎， 视网膜变性将减缓光感受器损失的进展并稳定/修复继发性血管损伤。 通过促进旁分泌和自分泌介质的释放来调节病理学。具体目标如下： 建议：（1）确定MSC治疗早期阶段的剂量反应和长期安全性和有效性， （2）研究MSCs在RCS大鼠神经退行性变后期的神经血管保护作用。 RCS大鼠和Elov 14小鼠中MSC的变性;（3）检查MSC归巢至 视网膜和静脉给药后的疗效。基于目前广泛的临床经验 使用MSC作为再生和退行性医学的治疗，如果在 在动物模型中，这种治疗具有转化为临床的现实可能性。

Summary 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.