DNA Delivery for Treatment of Proliferative Vitreoretinopathy and Ocular Scarring

DNA 递送治疗增殖性玻璃体视网膜病变和眼部疤痕

• 批准号: 7573652
• 负责人: Horst A. von Recum
• 金额: $ 23.55万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7573652
• 关键词: Address; Age related macular degeneration; Antisense Oligonucleotides; Apoptosis; Area; Biological; Biological Assay; Cataract; Cataract Extraction; Cell Culture Techniques; Cell Line; Cell Survival; Cell model; Cells; Cicatrix; Clinic; Clinical; Code; Cornea; DNA; DNA delivery; Data; Dendrimers; Diabetic Retinopathy; Disease; Drug Delivery Systems; Drug Formulations; Encapsulated; Environment; Eye; Eye diseases; Familiarity; Fiber; Fibroblasts; Fluorescence; Fluorescence Microscopy; Future; Gene Expression; Gene Silencing; Glaucoma; Goals; Green Fluorescent Proteins; Half-Life; Human; Implant; Investigation; Kinetics; Laboratories; Lead; Liposomes; Liquid substance; Macular degeneration; Micelles; Modeling; Nucleic Acids; Oligonucleotides; Operative Surgical Procedures; Outcome; Patient Care; Peptides; Pharmaceutical Preparations; Phase; Polymers; Predisposition; Process; Proliferative Vitreoretinopathy; Public Health; Research; Research Personnel; Simulate; Small Interfering RNA; Solutions; Staining method; Stains; Surface; System; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Transfection; Transforming Growth Factor beta; Translations; Up-Regulation; Vascular Endothelial Growth Factors; Western Blotting; Work; annexin A5; aptamer; aqueous; base; biodegradable polymer; compliance behavior; controlled release; corneal scar; cost; effective therapy; glaucoma surgery; in vivo; innovation; knock-down; nanofiber; nanoscale; nanosized; novel; novel therapeutics; overexpression; pressure; protein expression; public health relevance; scaffold; small molecule; success; vector

DESCRIPTION (provided by applicant): While many new therapeutic molecules for treatment of ocular diseases have become available over the past decade, one of the major problems facing their effective application in clinic has been drug delivery. Often bioactive molecules have a short half-life in vivo and require repeated administration. In the case of intraocular administration this often means poor patient compliance and high cost. As such, controlled release of therapeutic molecules over a period of months to years is expected to have a significant impact in patient care and in the treatment of ocular disease. The focus of this proposal is to investigate micro and nanoscale polymer fibers for the intraocular delivery of therapeutic molecules. Fibers have an advantage over other nano and microscale delivery vectors in that they can be moved or removed if complications arise. One of the primary targets implicated in several ocular diseases is Transforming Growth Factor - beta (TGF-¿). These diseases include corneal scarring, scarring following cataract and glaucoma surgery, as well as proliferative vitreoretinopathy. Decreasing TGF-¿ expression and its effect through use of antisense oligonucleotides, aptamers and other small molecule drugs has shown some success in treatment of these diseases. While delivery of siRNA against TGF-¿ has also been demonstrated to be effective, siRNA is limited as a long term therapy due to its susceptibility to ubiquitous RNAses as well as the need to have a large number of molecules for effective knockdown in vivo. In this study we propose to examine delivery of DNA which codes for the siRNA to knockdown TGF-¿ expression. Delivery of DNA addresses issues of stability since DNA is much more stable than RNA, and addresses issues of drug amount since a single DNA molecule can be transcribed into many siRNAs. The objective of the proposed research is to develop a microscale drug delivery platform which can easily be implanted to treat a wide range of ocular diseases. Specifically the hypothesis of this study is that the proposed therapeutic DNA can be incorporated and released from polymer nanofibers, and that released DNA can result in expression knockdown in ocular cell models. The hypothesis will be tested in three specific aims: 1) Evaluate the bioactivity of DNA released from nanofibers formed by electrospinning, 2) In a destabilized GFP model evaluate effect of released DNA in knocking down expression, and 3) In a human corneal fibroblast model evaluate the effect of released DNA in knockdown of TGF-¿ expression. This ocular model was chosen due to the investigators' familiarity with it. However, a drug delivery platform which can successfully deliver therapeutic DNA against one disease could rapidly be applied toward treatment of other diseases, such as VEGF knockdown in wet-type macular degeneration, or in diabetic retinopathy. PUBLIC HEALTH RELEVANCE: This proposal is critically concerned with the issue of public health in that its long term goal is to provide a drug delivery platform for providing sustained release of molecules to treat intraocular diseases. The short term goal is whether polymer nanofibers can deliver DNA to knock down expression of TGF-¿ in cell culture models of intraocular scarring disorders including corneal scarring, post-surgical scarring, and proliferative vitreoretinopathy.

描述（由申请人提供）：在过去的十年中，虽然有许多新的治疗眼疾的治疗分子出现，但它们在临床中的有效应用面临的主要问题之一是药物传递。通常生物活性分子在体内的半衰期很短，需要反复给药。在眼内给药的情况下，这通常意味着患者依从性差和成本高。因此，在几个月到几年的时间内，治疗分子的控制释放预计将对患者护理和眼病治疗产生重大影响。本研究的重点是研究微纳米级聚合物纤维用于治疗性分子的眼内递送。与其他纳米和微尺度的输送载体相比，纤维的优势在于，如果出现并发症，它们可以被移动或移除。