A Novel Treatment for Keratoconus and Keratectasias using Nitro Technology
使用硝基技术治疗圆锥角膜和角膜扩张症的新方法
基本信息
- 批准号:7754376
- 负责人:
- 金额:$ 19.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-01-01 至 2011-06-30
- 项目状态:已结题
- 来源:
- 关键词:AnimalsApoptosisBiologicalBiological AssayBiomechanicsBlindnessCell CountCellsClinical TrialsCollagenCommunitiesConfocal MicroscopyCorneaCorneal DiseasesCorneal EndotheliumCorneal TopographyDiseaseDoseEndothelial CellsEpidemiologyEpithelialEpithelial CellsEuropeanEyeEye BanksEyedropsFemaleGerman populationGlutaralGoalsGrantHeart ValvesHistologyHumanIn VitroIncubatedIntellectual PropertyInternationalKeratoconusLaboratoriesLaser In Situ KeratomileusisLegal patentLifeMechanicsMethodsMicroscopeMonitorNecrosisNew ZealandNitritesNitro CompoundsOperative Surgical ProceduresOryctolagus cuniculusPatientsPenetrationPeripheralPhase I Clinical TrialsPhysiologic Intraocular PressureProceduresProperty RightsProsthesisPublishingReactionResearchResearch PersonnelRiboflavinRiskSafetySelf AdministrationSimulateSkin TransplantationSkin graftSolutionsTechniquesTechnologyTemperatureTestingThickTissuesToxic effectTranslationsTransplanted tissueUltraviolet RaysUniversitiesWorkbasecatalystcell growthcostcrosslinkcytotoxicitydesignimplantationin vivoinstrumentmembernew technologynovelpublic health relevanceresearch studyresponsesuccesstonometryultraviolet irradiationvision scienceyoung adult
项目摘要
DESCRIPTION (provided by applicant): A major breakthrough in the treatment of keratoconus and post-LASIK keratectasias has been realized. Recent work by the German group of Wollensak, Spoerl, and Seiler has shown that cross-linking corneal collagen through application of riboflavin and ultraviolet light (UVR) can limit progressive vision loss in keratoconus patients. Despite these successes, the UVR therapy poses attendant risks, particularly related to ultraviolet irradiation. As such, FDA approval for clinical trials in the US has only recently been granted. The thrust of this application is to develop an alternative method of corneal collagen cross-linking using novel technology. Our recent studies indicate that collagen cross-linking through reactions with nitrite and related agents can induce corneal changes commensurate with UVR therapy. In addition, published toxicity/mutagenicity studies suggest a good safety profile for these agents. Thus, nitro technology could be used as an "eye drop alternative" to UVR treatment. Potential advantages over current UVR therapy include the omission of ultraviolet light exposure, the ability to treat thin corneas, less patient discomfort, ease of self- administration, a dose-response effect, and the ability to treat the peripheral cornea. This project is designed to lay groundwork for rapid translation of this technology into a treatment. Specifically, we will: 1. Determine an effective way to cross-link the cornea using nitro technology under conditions simulating the human cornea (i.e. pH 7.4 and 34oC). Fresh rabbit and human eye bank corneas will be incubated under a variety of conditions that include 1. nitrite with catalysts and 2. alternative nitrite related agents. The assay of thermal shrinkage temperature will be used to determine cross-linking efficacy. Stiffness changes induced will be studied using a biaxial material tester. Specific aim 1 is designed to identify one or more "candidate eye drops" that will then be used for in vivo rabbit experiments. 2. Test the hypothesis that corneal cross-linking through nitro technology is tolerated by corneal cells. Primary cultures of rabbit endothelial cells, keratocytes, and epithelial cells will be grown in vitro. The cells will then be exposed to nitro compounds found to be efficacious for cross-linking. Cytotoxicity will be evaluated using standard apoptosis and necrosis assays. The results from this aim will establish the in vitro toxicity level of nitro compounds to corneal cells. Specific aim 3. Test the hypothesis that corneal cross-linking through nitro technology has efficacy and is safe for the living eye. 33 young adult female New Zealand white rabbits will undergo daily application (for 1-6wks) of the topical nitro solution to the right eye with the fellow eye serving as a control. The animals will undergo serial examinations using 3 non-invasive instruments, a corneal topographer, in vivo confocal microscope, and applanation tonometer. Post-mortem, biomechanical strength testing, histology, and SEM will be performed. The results of this aim will establish the in vivo efficacy and safety of this technology and will dictate the feasibility of a human phase I trial. PUBLIC HEALTH RELEVANCE This research aims to develop a simple, new treatment for diseases of corneal destabilization which include keratoconus and post-surgical keratectasias. The latter conditions are devastating, long-term (5-10 years) complications following LASIK procedures. They were previously unpredicted and are currently of unknown epidemiologic proportion.
描述(申请人提供):圆锥角膜和LASIK术后角膜扩张症的治疗已经实现了重大突破。德国Wollensak、Spoerl和Seler小组最近的研究表明,通过应用核黄素和紫外线(UVR)使角膜胶原交联可以限制圆锥角膜患者的进行性视力损失。尽管取得了这些成功,但UVR疗法也带来了随之而来的风险,特别是与紫外线照射有关的风险。因此,FDA最近才批准在美国进行临床试验。这项应用的主旨是利用新技术开发一种替代角膜胶原交联剂的方法。我们最近的研究表明,胶原通过与亚硝酸盐及相关物质的反应而交联,可以引起与UVR治疗相称的角膜变化。此外,已发表的毒性/致突变性研究表明,这些制剂具有良好的安全性。因此,硝基技术可以作为紫外线治疗的“眼药水替代品”。与目前的UVR疗法相比,UVR疗法的潜在优势包括避免紫外线照射,治疗薄角膜的能力,患者较少的不适,易于自我给药,剂量反应效应,以及治疗周边角膜的能力。该项目旨在为将这项技术快速转化为治疗方法奠定基础。具体来说,我们将:1.确定一种在模拟人类角膜的条件下(即pH 7.4和34oC)使用硝基技术进行角膜交联的有效方法。新鲜的兔和人眼库角膜将在各种条件下孵化,包括1.有催化剂的亚硝酸盐和2.替代亚硝酸盐相关的试剂。热收缩温度的测定将用来确定交联剂的效果。将使用双轴材料试验机来研究引起的刚度变化。特殊目的1旨在识别一种或多种“候选眼药水”,然后用于活体兔子实验。2.验证角膜细胞可耐受通过硝基技术进行的角膜交联化的假设。兔内皮细胞、角质形成细胞和上皮细胞的原代培养将在体外培养。然后,这些细胞将暴露在被发现对交联有效的硝基化合物中。细胞毒性将使用标准的细胞凋亡和坏死分析进行评估。这一目标的结果将确定硝基化合物对角膜细胞的体外毒性水平。具体目的3.验证通过硝基技术进行的角膜交联术对活体眼睛有效且安全的假设。33只年轻成年雌性新西兰白兔每天(1-6周)在右眼局部涂抹硝化液,对侧眼作为对照。实验动物将使用3种非侵入性仪器--角膜地形图仪、活体共聚焦显微镜和压平式眼压计进行一系列检查。将进行尸检、生物力学强度测试、组织学和扫描电子显微镜检查。这一目标的结果将确定这项技术的体内有效性和安全性,并将决定人类I期试验的可行性。公共卫生相关性这项研究旨在开发一种简单的新疗法来治疗角膜不稳定的疾病,包括圆锥角膜和术后角膜扩张。后一种情况是LASIK手术后破坏性的长期(5-10年)并发症。它们以前是不可预测的,目前的流行病学比例尚不清楚。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Nitroalcohol Induced Hydrogel Formation in Amine-Functionalized Polymers.
- DOI:10.1002/app.31944
- 发表时间:2010-07-15
- 期刊:
- 影响因子:3
- 作者:Solomon, Marissa R.;O'Connor, Naphtali A.;Paik, David C.;Turro, Nicholas J.
- 通讯作者:Turro, Nicholas J.
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DAVID C PAIK其他文献
DAVID C PAIK的其他文献
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{{ truncateString('DAVID C PAIK', 18)}}的其他基金
Therapeutic Corneal Cross-linking Using Aliphatic Beta-Nitroalcohols
使用脂肪族 β-硝基醇进行治疗性角膜交联
- 批准号:
8616069 - 财政年份:2011
- 资助金额:
$ 19.8万 - 项目类别:
Therapeutic Corneal Cross-linking Using Aliphatic Beta-Nitroalcohols
使用脂肪族 β-硝基醇进行治疗性角膜交联
- 批准号:
8228144 - 财政年份:2011
- 资助金额:
$ 19.8万 - 项目类别:
Therapeutic Corneal Cross-linking Using Aliphatic Beta-Nitroalcohols
使用脂肪族 β-硝基醇进行治疗性角膜交联
- 批准号:
8435517 - 财政年份:2011
- 资助金额:
$ 19.8万 - 项目类别:
Therapeutic Corneal Cross-Linking Using Formaldehyde Releasing Agents
使用甲醛释放剂进行治疗性角膜交联
- 批准号:
9106336 - 财政年份:2011
- 资助金额:
$ 19.8万 - 项目类别:
Therapeutic Corneal Cross-linking Using Aliphatic Beta-Nitroalcohols
使用脂肪族 β-硝基醇进行治疗性角膜交联
- 批准号:
8040254 - 财政年份:2011
- 资助金额:
$ 19.8万 - 项目类别:
Therapeutic Corneal Cross-Linking Using Formaldehyde Releasing Agents
使用甲醛释放剂进行治疗性角膜交联
- 批准号:
9233107 - 财政年份:2011
- 资助金额:
$ 19.8万 - 项目类别:
A Novel Treatment for Keratoconus and Keratectasias using Nitro Technology
使用硝基技术治疗圆锥角膜和角膜扩张症的新方法
- 批准号:
7588578 - 财政年份:2009
- 资助金额:
$ 19.8万 - 项目类别:
NITRITE/COLLAGEN REACTIONS IN AGING AND SMOKING
衰老和吸烟中的亚硝酸盐/胶原蛋白反应
- 批准号:
6629663 - 财政年份:2000
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$ 19.8万 - 项目类别:
NITRITE/COLLAGEN REACTIONS IN AGING AND SMOKING
衰老和吸烟中的亚硝酸盐/胶原蛋白反应
- 批准号:
6044277 - 财政年份:2000
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$ 19.8万 - 项目类别:
NITRITE/COLLAGEN REACTIONS IN AGING AND SMOKING
衰老和吸烟中的亚硝酸盐/胶原蛋白反应
- 批准号:
6509365 - 财政年份:2000
- 资助金额:
$ 19.8万 - 项目类别:
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