Pharmacological Suppression of Rod Opsin as Therapy for Retinitis Pigmentosa

杆状视蛋白的药理学抑制治疗色素性视网膜炎

基本信息

批准号：
8516861
负责人：
Scott McNear Thacher
金额：
$ 22.45万
依托单位：
ORPHAGEN PHARMACEUTICALS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516861
关键词：
3-Dimensional Adult Affect Age American Animal Model Biological Assay Blindness Cell Culture Techniques Cell Death Cellular Stress Chemistry Clinical Complete Blindness Computer Simulation Development Disease Dominant-Negative Mutation Dose Drug Formulations Event Eye Gene Dosage Gene Expression Gene Mutation Genes Genetic Goals Hereditary Disease Inherited Inhibitory Concentration 50 Injection of therapeutic agent Lead Libraries Life Ligands Measures Mediating Messenger RNA Methods Modeling Modification Mus Mutation Neonatal Nervous system structure Nuclear Receptors Opsin Orphan Pathway interactions Patients Phagocytosis Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenotype Photoreceptors Precipitation Probability Process Proteins Publishing RNA Splicing Rattus Retina Retinal Retinal Degeneration Retinal Diseases Retinal Photoreceptors Retinitis Pigmentosa Retinoids Rhodopsin Rodent Rodent Model Series Small Business Innovation Research Grant Solubility Structure Structure of ciliary processes Testing Toxic effect Treatment Efficacy Work activating transcription factor aged base ciliopathy compound 30 design efficacy testing gene therapy improved in vivo intravitreal injection member mouse model mutant novel pharmacophore photoreceptor degeneration public health relevance receptor response retina outer nuclear layer retinal rods rho safety study scaffold small molecule trafficking transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Retinitis pigmentosa (RP), a hereditary disease of the retina affecting 100,000 Americans, is the major cause of blindness in adults aged 25-60. There is no approved therapy for the disease and gene therapy, while promising, is limited because of the diversity of underlying genetic mutations. The abnormal localization of rod opsin, the highly-expressed major protein constituent of the photoreceptor outer segment, has long been recognized as a major event preceding photoreceptor cell death in animal models of RP. Recently, in two mouse models of ciliopathy, a reduction in rod opsin expression by genetic methods was shown to markedly delay what is otherwise a rapid loss of photoreceptors in the outer nuclear layer of the retina. Orphagen has discovered specific small molecule ligands to a previously unexplored orphan receptor that is expressed in the photoreceptor layer and is essential for early retinal development. In primary neonatal rat retinal cultures, antagonists (IC50 < 250 nM) to this receptor partially suppress rod opsin expression in a receptor-specific manner. After intravitreal injection in rats, our current probe compound also significantly suppresses rod opsin mRNA. The findings suggest that a clinical antagonist to the same receptor will reduce the rate of photoreceptor degeneration for the estimated 40% of RP patients where mislocalization of rod opsin is a factor in rod photoreceptor cell death. In response to PAR-09-260, Optimization of Small Molecule Probes for the Nervous System, we propose to identify a substantially more potent antagonist necessary for in vivo proof-of-principle studies. Two consecutive daily 5 mg intravitreal injections of the current probe compound cause a modest 25% suppression of rod opsin mRNA. However, the potency of the current probe compound is too low for development of an experimental slow release formulation that could deliver an effective intraocular dose over four weeks, a duration required to measurably inhibit photoreceptor degeneration in many rodent RP models. In Aim 1, we identify new receptor antagonist scaffolds, from commercial compound libraries, based on a 3-D computational model of the proprietary antagonists developed at Orphagen, in order to expand starting points for subsequent medicinal chemistry; in Aim 2, we carry out focused medicinal chemistry to increase potency with the goal of achieving an IC50 < 40 nM for rod opsin suppression in primary retinal cultures; and in Aim 3, we select a lead compound with improved potency and efficacy (rod opsin mRNA inhibition >30% at ¿ 1 mg/ intravitreal injection) and evaluate retinal function (determined by ERG) to exclude retinal toxicity. If Phase 1 SBIR aims are successfully completed, we plan in Phase 2 to formulate the lead receptor antagonist for sustained intravitreal release and to carry out efficacy and safety studies in rodent models of RP that would justify initiating development of this novel drug class for clinical use.

描述（由申请人提供）：色素性视网膜炎 (RP) 是一种影响 100,000 名美国人的视网膜遗传性疾病，是 25-60 岁成年人失明的主要原因。目前尚无针对该疾病的批准疗法和基因疗法，但前景乐观。由于潜在基因突变的多样性，视杆细胞视蛋白（光感受器外节的高表达主要蛋白质成分）的异常定位长期以来被认为是一种限制。 RP动物模型中光感受器细胞死亡之前的主要事件最近，在两种纤毛病小鼠模型中，通过遗传方法减少视杆细胞视蛋白表达可显着延缓视网膜外核层中光感受器的快速丧失。 Orphagen 发现了一种先前未开发的孤儿受体的特定小分子配体，该受体在光感受器层中表达，并且在原代新生大鼠视网膜培养物中对于早期视网膜发育至关重要。 (IC50 < 250 nM) 该受体以受体特异性方式部分抑制视杆细胞视蛋白的表达。在大鼠玻璃体内注射后，我们目前的探针化合物也显着抑制视杆细胞视蛋白的 mRNA。研究结果表明，相同受体的临床拮抗剂将显着抑制视杆细胞视蛋白的表达。降低估计 40% 的 RP 患者的光感受器变性率，其中视杆细胞视蛋白的错误定位是视杆细胞光感受器细胞死亡的一个因素响应 PAR-09-260，用于神经系统的小分子探针的优化，我们建议鉴定一种体内原理验证所需的更有效的拮抗剂每日两次连续注射 5 mg 当前探针化合物可对视杆蛋白 mRNA 产生适度的 25% 抑制，但是，当前探针化合物的效力太低，无法开发出可提供有效效果的实验性缓释制剂。眼内剂量超过 4 周，这是在许多啮齿动物 RP 模型中可测量地抑制光感受器变性所需的持续时间。在目标 1 中，我们基于 3-D 计算从商业化合物库中识别出新的受体拮抗剂支架。 Orphagen 开发的专有拮抗剂模型，为了扩大后续药物化学的起点；在目标 2 中，我们进行了集中药物化学以提高效力，目标是在原发性视网膜中实现杆状视蛋白抑制的 IC50 < 40 nM在目标 3 中，我们选择一种具有改进效力和功效的先导化合物（玻璃体内注射 1 mg 时，视杆细胞视蛋白 mRNA 抑制 >30%）并评估视网膜如果第一阶段 SBIR 目标成功完成，我们计划在第二阶段制定用于持续玻璃体内释放的主要受体拮抗剂，并在 RP 啮齿动物模型中进行有效性和安全性研究。证明启动这种新型药物类别的临床应用开发是合理的。