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退化性疾病。在我们关于视网膜发育表观遗传调节的研究过程中，我们有定义了组蛋白修饰可以将这些机制锁定为无活性的基因的方法冷凝染色质。我们发现许多药物部分反向染色质冷凝而没有任何正常细胞功能的明显丧失。更重要的是，这些表观遗传修饰剂可预防感光体视网膜炎色素炎模型的变性。除了组织学和分子保存外，治疗还降低了视力丧失和对比度灵敏度。基于我们出版的初步研究，我们假设这些药物可用于逆转染色质凝结并允许感光体应对疾病胁迫的反应和生存。这种针对视网膜的创新方法通过染色质压实变化的变性具有很强的翻译意义，因为它是突变独立的。从我们的研究中，我们选择了一名主要候选人，现在提出了两个具体目标来解决有关感光体变性的重要科学问题。第一个是有效输送该药物。表观遗传修饰药通常显示出全身性副作用。局部针对眼睛的目标会阻止达到此类效果的阈值的全身浓度。第二，尽管我们有数据支持我们的假设，即染色质脱凝性是表观遗传修饰药的关键作用，因此对于许多光感受器变性，我们尚未使用不同模型测试疗效色素性视网膜炎和与年龄相关的黄斑变性（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测试最有效的局部治疗的剂量和频率阻止了C57BL/6RD10突变小鼠的杆变性。在第二个目标中，我们将测试GSK2879552在另外两种型号的感光器模型上的功效变性，即Rho-P23H转基因小鼠，色素性视网膜炎的附加模型和 ABCA4 - / - RDH8 - / - 双基因敲除鼠标，ARMD型号。这些目标的结果将定义我们的假设，重要机制和光感受器变性的处理，并有助于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提出一组关键使用GMP级材料的II期研究，包括全身毒性筛查，给药，配方和生物稳定性研究将使我们迈向IND申请和人类试验。