Novel cell-based Restorative Approach in Treatment of Diabetes-related Retinopath

治疗糖尿病相关视网膜病变的新型细胞修复方法

• 批准号: 8646520
• 负责人: LEONARD P MILLER
• 金额: $ 21.57万
• 依托单位: TARGAZYME, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646520
• 关键词: Address; Adhesions; Adult; Albumins; Americas; Animal Model; Area; Autologous; Binding; Biological Assay; Blindness; Blood Vessels; Blood flow; Bone Marrow; CD34 gene; Cell surface; Cells; Clinical Trials; Cyclic GMP; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Dose; Endothelial Cells; Enzymes; Epidemic; Exhibits; Exposure to; Extravasation; Eye; Florida; Fucose; Funding; Guanosine Diphosphate Fucose; Hematopoietic; High Pressure Liquid Chromatography; Homing; Immune; In Vitro; Incidence; Injection of therapeutic agent; Injury; Insulin-Dependent Diabetes Mellitus; Ischemia; Lasers; Lead; Lesion; Ligands; Measures; Mediating; Medical; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Natural regeneration; Nature; Neuraminidase; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Patients; Physiological; Preparation; Prevalence; Procedures; Production; Reagent; Recovery; Reperfusion Injury; Reperfusion Therapy; Research; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Role; Selectins; Small Business Innovation Research Grant; Societies; Stem cells; Technology; Therapeutic; Tissues; Vascular Diseases; adult stem cell; base; bevacizumab; clinical application; defined contribution; diabetic; diabetic patient; enzyme substrate; functional improvement; improved; in vivo; legally blind; macular edema; neovascularization; new technology; novel; patient population; peripheral blood; public health relevance; relating to nervous system; repaired; research study; response; restoration; retina blood vessel structure; retinal damage; retinal ischemia; stem; stem cell population; sugar; treatment effect

DESCRIPTION (provided by applicant): Retinal vascular diseases remain a common cause of vision loss and blindness with diabetes as the most common condition leading to retinopathy in adults in Western society. In particular, with type 1 diabetes the majority of patients will develo diabetic retinopathy (DR) with about 20-30% becoming legally blind while in type 2 diabetes more than 60% of patients will exhibit DR. With the well-documented global epidemic of type 2 diabetes, DR is likely to increase in incidence and prevalence since over 360 million people world-wide are projected to suffer from diabetes by 2030. Although therapies such as anti-VEGF agents and laser are currently available to treat macular edema and neovascularization, there is no treatment that regenerates damaged retinal vasculature with reestablishment of critical levels of blood flow needed to support & sustain recovery. Research over the last decade has shown that peripheral blood (PB)-derived CD34+ stem/progenitor cells are capable of homing to vascular lesions in the eye and contribute to vascular repair. Unfortunately, though in diabetic patients these CD34+ cells are defective as reflected by a profound inability to migrate in vitro due to an adhesion deficit. To overcome this deficit we explored the effect of treatment with a new technology, ASC-101, from America Stem Cell (ASC). Our preliminary in vivo studies with mice show that ASC-101-mediated fucosylation of PB-derived CD34+ cells obtained from diabetic patients led to enhanced homing of these cells to damaged retinal vessels post ischemia/reperfusion (I/R) by comparison to controls. Our present SBIR submission will extend on these initial exciting proof-of-concept results with the identification of optimal parameters fo application along with defining the enduring nature and functional significance of this apparent restorative effect. Thus, we have outlined three specific aims: 1.Manufacture research-grade ASC-101 and substrate, GDP-fucose 2.Optimize treatment parameters, profile enduring effect & confirm role of homing to enhanced effect. 3.Examine for functional improvement Positive results from our presently proposed experiments will support subsequent submission of an SBIR II to conduct additional studies further addressing application of this novel stem-cell-based approach in addition to addressing IND-enabling activities in preparation for an eventual clinical trial involving patients with retinal disease.

描述（由申请人提供）：视网膜血管疾病仍然是视力丧失和失明的常见原因，而糖尿病是导致西方社会成年人视网膜病变的最常见疾病。特别是，对于 1 型糖尿病，大多数患者将出现糖尿病视网膜病变 (DR)，其中约 20-30% 的患者在法律上失明，而对于 2 型糖尿病，超过 60% 的患者将出现 DR。随着 2 型糖尿病在全球范围内的流行，预计到 2030 年，全球将有超过 3.6 亿人患有糖尿病，因此 DR 的发病率和患病率可能会增加。尽管目前抗 VEGF 药物和激光等治疗方法尚未成熟。虽然可用于治疗黄斑水肿和新生血管形成，但没有任何治疗方法可以使受损的视网膜脉管系统再生，并重建支持和维持恢复所需的关键血流水平。 过去十年的研究表明，外周血 (PB) 来源的 CD34+ 干/祖细胞能够归巢到眼部血管病变处并有助于血管修复。不幸的是，尽管在糖尿病患者中，这些 CD34+ 细胞是有缺陷的，这反映在由于粘附缺陷而无法在体外迁移。为了克服这一缺陷，我们探索了美国干细胞 (ASC) 新技术 ASC-101 的治疗效果。我们对小鼠的初步体内研究表明，与对照组相比，从糖尿病患者获得的 PB 衍生 CD34+ 细胞的 ASC-101 介导的岩藻糖基化导致这些细胞在缺血/再灌注 (I/R) 后增强归巢到受损的视网膜血管。 我们目前提交的 SBIR 提案将扩展这些最初令人兴奋的概念验证结果，确定应用的最佳参数，并定义这种明显恢复效果的持久性质和功能意义。因此，我们概述了三个具体目标： 1. 制造研究级 ASC-101 和底物 GDP-岩藻糖 2. 优化治疗参数，分析持久效果并确认归巢至增强效果的作用。 3.检查功能改进我们目前提出的实验的积极结果将支持随后提交 SBIR II，以开展更多研究，进一步解决这种新型干细胞方法的应用，此外还解决 IND 启用活动，为最终的涉及视网膜疾病患者的临床试验。