Nanoparticle-based therapy for photoreceptor degeneration

基于纳米颗粒的光感受器变性疗法

• 批准号: 9054243
• 负责人: VINOD D LABHASETWAR
• 金额: $ 39.63万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054243
• 关键词: Accounting; Affect; Age; Antioxidants; Apoptosis; Apoptotic; Biochemical Process; Biological Preservation; Biology; Blindness; Cell Count; Cell Death; Cells; Child; Childhood; Chronic; Complex; Development; Disease; Disease Progression; Dose; Effectiveness; Electroretinography; Encapsulated; Environment; Evaluation; Event; Free Radicals; Gene Mutation; Generations; Genes; Genetic; Goals; Human; In Situ Nick-End Labeling; Individual; Inflammatory Response; Inheritance Patterns; Inherited; Intraperitoneal Injections; Light; Mediating; Modeling; Mus; Mutation; Omega-3 Fatty Acids; Outcome Measure; Oxidative Stress; Oxygen; Pathway interactions; Patients; Phenotype; Photoreceptors; Play; Prevalence; Property; Proteins; Reactive Oxygen Species; Research; Retina; Retinal; Retinal Cone; Retinal Diseases; Retinitis Pigmentosa; Rhodopsin; Role; Signal Transduction; Staging; Structure; Superoxide Dismutase; Techniques; Testing; Therapeutic Agents; Time; Tissues; Treatment Protocols; Vertebrate Photoreceptors; Vision; Visual impairment; Vitamin A; Work; antioxidant enzyme; base; catalase; clinical practice; density; driving force; early onset; endoplasmic reticulum stress; gene replacement therapy; human disease; intraperitoneal; light microscopy; mouse model; nano; nanoparticle; oxidative damage; peripherin; photoreceptor degeneration; postnatal; public health relevance; response; retinal rods; rho; stressor; therapy development

 DESCRIPTION (provided by applicant): By encapsulating therapeutic agents within biodegradable nanoparticles, it is possible to provide long-lasting delivery of molecules that are otherwise rapidly cleared or degraded. The purpose of this proposal is to continue evaluation and development of a nanoparticle platform with which to deliver antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT) (nano-SOD/CAT) to treat retinal diseases. Oxidative damage mediated via reactive oxygen species (ROS) is an important driving force in photoreceptor degeneration as occurs in human retinal diseases such as retinitis pigmentosa (RP). We have found that "systemic delivery (intraperitoneal injection)" of nano-SOD/CAT significantly slows the rate of photoreceptor cell death in a widely used very aggressive model of human RP - the Pdeb6rd10 (rd10) mouse. To build upon these promising results, we will test the hypothesis that nano-SOD/CAT is effective in slowing the rate of photoreceptor cell death for many genetic forms of RP and can be developed as a chronic therapy to slow down disease progression. In Aim 1, we will define the optimal dose of nano-SOD/CAT, determine which treatment schedule provides the best results, and will also examine whether the beneficial effect of nano-SOD/CAT application is dependent upon the age (disease stage) when treatment begins. In all of these studies, we will evaluate retinal function using electroretinogram (ERG) recordings and retinal structure using light microscopy and by counting the number of cells undergoing apoptosis. In Aim 2, we will inhibit two pathways that play major roles in cellular events initiated by oxidative stress. These studies will use the same outcome measures as Aim 1, and will clarify the mechanism(s) by which nano-SOD/CAT mediated reduction in ROS leads to preservation of photoreceptors. In Aim 3, we will expand this research strategy to three additional mouse models. While human RP is caused by mutations in more than 50 genes, mutations in rhodopsin and peripherin/rds account for a sizeable fraction of affected patients. Therefore, we will determine whether nano-SOD/CAT will slow the degenerative phenotype in three mouse models for autosomal recessive or dominant RP due to Rho or Prhp2 mutations. These mouse models were chosen due to their underlying genetics and their distinct rates of photoreceptor cell loss, all of which are slower than that seen in the rd10 model. Aim 3 will thus provide important information about the general potential for nano-SOD/CAT to slow the rate of photoreceptor degeneration in multiple genetic forms of RP with distinct phenotypes which are also commonly seen in humans. Although nano-SOD/CAT will not correct the underlying genetic defect, significant disease slowing would be meaningful, by allowing affected patients, particularly children to retain useful vision for a substantially longer period of time and potentilly throughout their lifetime.

 描述（由申请人提供）：通过将治疗剂封装在可生物降解的纳米颗粒内，可以提供否则会被快速清除或降解的分子的持久递送。该提案的目的是继续评估和开发纳米颗粒平台。提供抗氧化酶、超氧化物歧化酶 (SOD) 和过氧化氢酶 (CAT)（纳米 SOD/CAT）来治疗活性氧介导的氧化损伤。 ROS（ROS）是人类视网膜疾病（例如色素性视网膜炎（RP））中感光细胞变性的重要驱动力。我们发现纳米 SOD/CAT 的“全身递送（腹膜内注射）”显着减慢了感光细胞的速率。在广泛使用的非常具有攻击性的人类 RP 模型 - Pdeb6rd10 (rd10) 小鼠中死亡 为了建立在这些有希望的结果的基础上，我们将测试纳米 SOD/CAT 是否有效的假设。可以减缓许多遗传形式的 RP 的感光细胞死亡速度，并且可以开发为减缓疾病进展的慢性疗法。在目标 1 中，我们将确定纳米 SOD/CAT 的最佳剂量，确定提供哪种治疗方案。最佳结果，并且还将检查纳米 SOD/CAT 应用的有益效果是否取决于治疗开始时的年龄（疾病阶段）。在所有这些研究中，我们将使用视网膜电图 (ERG) 记录和评估视网膜功能。在目标 2 中，我们将使用光学显微镜观察视网膜结构并计算细胞凋亡的数量，这些研究将使用与目标 1 相同的结果测量方法，抑制在氧化应激引发的细胞事件中发挥主要作用的两条途径。阐明纳米 SOD/CAT 介导的 ROS 减少导致光感受器保存的机制。在目标 3 中，我们将这一研究策略扩展到另外三个小鼠模型，而人类 RP 是由 RP 突变引起的。超过 50 个基因，视紫红质和外周蛋白/rds 的突变占受影响患者的很大一部分，因此，我们将确定纳米 SOD/CAT 是否会减缓由 Rho 引起的常染色体隐性或显性 RP 的三种小鼠模型的退行性表型。选择这些小鼠模型是因为它们的潜在遗传学和不同的感光细胞损失率，所有这些都比 Aim 3 模型中看到的要慢。因此，提供了关于纳米 SOD/CAT 减缓具有不同表型的 RP 的光感受器变性速度的一般潜力的重要信息，尽管纳米 SOD/CAT 不会纠正潜在的遗传因素。缺陷，显着减缓疾病将是有意义的，让受影响的患者，特别是儿童在更长的时间内并在其一生中有效地保留有用的视力。