Epigenetic Modifiers to treat Photoreceptor Degenerations

表观遗传修饰剂治疗光感受器变性

基本信息

批准号：
10693776
负责人：
JOYCE TOMBRAN-TINK
金额：
$ 14.97万
依托单位：
SKYRAN BIOLOGICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10693776
关键词：
Address Age related macular degeneration Aging Animal Model Artificial Tears Biological Products Blindness Cell Survival Cell physiology Cells Cessation of life Chromatin Contrast Sensitivity Data Development Disease Dose Drug Delivery Systems Enzyme Inhibitor Drugs Enzymes Epigenetic Process Eye Eyedrops Formulation Frequencies Funding Future Genes Goals Histologic Histones Homozygote Human Injections Knock-out Knockout Mice Lead Marketing Measurement Microscopy Modeling Modification Molecular Mus Mutant Strains Mice Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Normal Cell Pathologic Pharmaceutical Preparations Phase Phenotype Photoreceptors Physical condensation Play Positioning Attribute Process Publishing Retina Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rod Role Stress Testing Therapeutic Tissues Topical application Toxic effect Transgenic Mice Up-Regulation Vision Visual Acuity autosome case control clinical development combat commercialization dosage efficacy evaluation efficacy testing epigenetic regulation epigenome experimental study histone modification improved inhibitor innovation insight lead candidate mouse model mutant neuroprotection novel therapeutics phase 2 study photoreceptor degeneration preservation prevent programs protective effect retinal neuron retinal rods screening side effect small molecule therapeutics systemic toxicity targeted delivery tool transcriptome sequencing translational approach

项目摘要

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.

抽象的： Skyran Biologics 的总体目标是开发强大的局部疗法来对抗视网膜病变退行性疾病。在我们对视网膜发育的表观遗传调控的研究过程中，我们发现定义了组蛋白修饰可以将编码这些机制的基因锁定为非活性的方式，浓缩染色质。我们发现许多药物可以部分逆转染色质凝聚，而无需任何药物正常细胞功能明显丧失。更重要的是，这些表观遗传修饰剂会阻止光感受器色素性视网膜炎模型中的变性。除了组织学和分子保存外，治疗还减少了视力和对比敏感度的损失。根据我们已发布的初步数据研究中，我们假设此类药物可用于逆转染色质凝聚并允许光感受器对疾病应激做出反应并存活下来。这种针对视网膜的创新方法通过染色质压缩变化引起的退化具有很强的翻译意义，因为它是突变独立的。根据我们的研究，我们选择了一位主要候选人，现在提出两个具体目标来解决关于光感受器变性的重要科学问题。首先是药物的有效输送。表观遗传修饰药物经常表现出全身副作用。局部有针对性地输送到眼睛将防止避免全身浓度达到此类效应的阈值。其次，虽然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，等等应该对许多感光器变性有效，我们尚未使用不同模型测试功效视网膜色素变性和年龄相关性黄斑变性（ARMD）。在我们的第一个特定目标中，我们将使用我们最有效的药物 GSK2879552 来测试最有效的药物阻止 C57Bl/6rd10 突变小鼠视杆细胞退化的局部治疗的剂量和频率。在我们的第二个目标中，我们将测试 GSK2879552 在另外两种感光器模型上的功效变性，即 Rho-P23H 转基因小鼠，另一种视网膜色素变性模型，以及 Abca4-/-Rdh8-/-双敲除小鼠，ARMD模型。这些目标的结果将定义以下的普遍性：我们的假设、光感受器变性的重要机制和治疗，以及帮助描述市场的潜在规模。成功完成这些目标所取得的里程碑将使我们能够提出一系列关键的建议使用 GMP 级材料的 II 期研究，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行 IND 申请和人体试验。