Epigenetic Modifiers to treat Photoreceptor Degenerations

摘要： Skyran Biologics的总体目标是开发强大的局部疗法来对抗视网膜 退行性疾病。在我们对视网膜发育的表观遗传调控的研究过程中，我们有 组蛋白修饰可以将编码这些机制的基因锁定为非活性的明确方式， 浓缩的染色质。我们发现了一些药物可以部分逆转染色质凝聚，但没有 正常细胞功能明显丧失。更重要的是，这些表观遗传修饰物阻止了光感受器 视网膜色素变性模型。除了组织和分子保存外， 治疗还减少了视力和对比敏感度的损失。基于我们发布的和初步的 研究，我们假设这种药物可以用来逆转染色质缩合，并允许 光感受器对疾病压力做出反应并存活下来。这种以视网膜为靶点的创新方法 染色质压缩的变化导致的退化具有很强的翻译含义，因为它是突变 独立自主。从我们的研究中，我们选择了一位主要候选人，现在提出了两个具体目标来解决 关于光感受器退化的重要科学问题。首先是药物的有效输送。 表观遗传修饰药物通常会出现全身副作用。局部靶向投放到眼睛将防止 系统集中度不会达到此类影响的阈值。第二，尽管我们有数据 支持我们的假设，即染色质解缩是表观遗传修饰药物的关键作用，因此 对于许多感光细胞退行性变应该是有效的，我们还没有使用不同的模型来测试效果 视网膜色素变性和老年性黄斑变性(ARMD)。 在我们的第一个具体目标中，我们将使用我们最有效的药物GSK2879552来测试最有效的 阻断C57BL/6rd10突变小鼠杆状退变的局部治疗剂量和频率。 在我们的第二个目标中，我们将在另外两个型号的感光器上测试GSK2879552的有效性 变性，即Rho-P23H转基因小鼠，另一种视网膜色素变性模型，以及 ABCA4-/-RDH8-/-双基因敲除小鼠，ARMD模型。这些目标的结果将定义 我们的假说，光感受器变性的重要机制和治疗，以及帮助描绘 市场的潜在规模。 成功完成这些目标所取得的里程碑将使我们能够提出一套关键的 使用GMP级材料的第二阶段研究，包括全身毒性筛选、剂量、配方和 生物稳定性研究将推动我们进入IND申请和人体试验。

Abstract: The overall goal of Skyran Biologics is to develop powerful topical therapeutics to combat retinal degenerative diseases. In the course of our studies on epigenetic regulation of retinal development we have defined ways in which histone modifications can lock genes encoding these mechanisms into inactive, condensed chromatin. We found a number of drugs that partially reverse chromatin condensation without any obvious loss of normal cell function. More importantly, these epigenetic modifiers prevent photoreceptor degeneration in models of Retinitis Pigmentosa. In addition to histological and molecular preservation, treatment also reduced loss of visual acuity and contrast sensitivity. Based on our published and preliminary studies, we hypothesize that such drugs can be used to reverse chromatin condensation and allow photoreceptors to respond to and survive disease stresses. This innovative approach to target retina degeneration through changes in chromatin compaction has a strong translational implication as it is mutation independent. From our studies, we selected a lead candidate and now propose two specific aims to address important scientific questions about photoreceptor degeneration. The first is effective delivery of the drug. Epigenetic modifier drugs often show systemic side effects. Topical targeted delivery to the eye will prevent systemic concentrations from reaching a threshold for such effects. Second, although we have data supporting our hypothesis that chromatin decondensation is the key effect of epigenetic modifier drugs, and so should be effective for many photoreceptor degenerations, we have not tested efficacy using different models of both Retinitis Pigmentosa and Age-Related Macular Degeneration (ARMD). In our first Specific Aim we will use our most potent drug, GSK2879552, to test the most effective dosage and frequency of topical treatment that blocks rod degeneration in C57Bl/6rd10 mutant mice. In our Second Aim we will test efficacy of GSK2879552 on two additional models of photoreceptor degeneration, namely the Rho-P23H transgenic mouse, an additional model of Retinitis Pigmentosa, and the Abca4-/-Rdh8-/- double knockout mouse, a model of ARMD. Results of these aims will define the generality of our hypothesis, important mechanisms and treatment of photoreceptor degeneration, as well as help delineate the potential size of the market. The milestones achieved by the successful completion of these aims will position us to propose a set of key Phase II studies using GMP grade material, including systemic toxicity screening, dosing, formulation, and biostability studies that will move us towards an IND filing and human trials.