Nanoparticle-based therapy for photoreceptor degeneration

 描述（由申请人提供）：通过将治疗剂包封在可生物降解的纳米颗粒内，可以提供分子的持久递送，否则这些分子会被快速清除或降解。该提案的目的是继续评估和开发纳米颗粒平台，通过该平台提供抗氧化酶，超氧化物歧化酶（SOD）和过氧化氢酶（CAT）（纳米SOD/CAT）来治疗视网膜疾病。通过活性氧（ROS）介导的氧化损伤是如在人类视网膜疾病如视网膜色素变性（RP）中发生的光感受器变性的重要驱动力。我们已经发现，纳米SOD/CAT的“全身递送（腹膜内注射）”显著减缓了广泛使用的非常具有攻击性的人RP模型-Pdeb 6 rd 10（rd 10）小鼠中感光细胞死亡的速率。为了建立在这些有希望的结果，我们将测试的假设，纳米SOD/CAT是有效地减缓感光细胞死亡的速度为许多遗传形式的RP，并可以开发作为一种慢性疗法，以减缓疾病的进展。在目标1中，我们将定义纳米SOD/CAT的最佳剂量，确定哪种治疗方案提供最佳结果，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）记录评估视网膜功能，并使用光学显微镜和计数经历凋亡的细胞数量来评估视网膜结构。在目标2中，我们将抑制在氧化应激引发的细胞事件中起主要作用的两种途径。这些研究将使用与目标1相同的结局指标，并将阐明纳米SOD/CAT介导的ROS减少导致光感受器保存的机制。在目标3中，我们将把这种研究策略扩展到另外三种小鼠模型。虽然人类RP是由超过50个基因的突变引起的，但视紫红质和外周蛋白/rds的突变占受影响患者的相当大一部分。因此，我们将确定纳米SOD/CAT是否会减缓由于Rho或Prhp 2突变导致的常染色体隐性或显性RP的三种小鼠模型中的退行性表型。选择这些小鼠模型是因为它们的潜在遗传学和感光细胞损失的不同速率，所有这些都比rd 10模型中看到的慢。因此，目标3将提供关于纳米SOD/CAT减缓具有不同表型的RP的多种遗传形式中的光感受器变性速率的一般潜力的重要信息，这些表型也常见于人类。虽然纳米SOD/CAT不会纠正潜在的遗传缺陷，但通过允许受影响的患者，特别是儿童在其一生中保持更长时间的有用视力，显著减缓疾病将是有意义的。

 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.