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：
8666826
负责人：
Scott McNear Thacher
金额：
$ 22.22万
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/8666826
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（由适用提供）：视网膜炎色素（RP）是一种影响100,000美国人的视网膜的遗传性疾病，是25-60岁成人失明的主要原因。由于基本基因突变的多样性，尚无对疾病和基因疗法的批准治疗。长期以来，在RP动物模型中，Rod Opsin的异常定位是光感受器外部段的高度表达的主要蛋白质构成的主要蛋白质。最近，在两种纤毛病的小鼠模型中，通过遗传学方法降低了ROD OPSIN表达，这显着延迟了视网膜外核层中光感受器的快速丧失。 Orphagen发现了在光感受器层中表达的以前出乎意料的孤儿受体的特定小分子配体，对于早期视网膜发育至关重要。在原发性新生儿大鼠视网膜培养物中，对该受体的拮抗剂（IC50 <250 nm）部分抑制了杆状蛋白的表达，以受体特异性方式抑制。玻璃体内注射大鼠后，我们的当前探针化合物还显着抑制了Rod Opsin mRNA。研究结果表明，对同一受体的临床拮抗剂将降低40％的ROD OPSIN的RP患者的40％患者的光感受器变性率，这是ROD光感受器细胞死亡的一个因素。为了响应PAR-09-260，对神经系统的小分子探针的优化，我们建议确定体内原理证明所需的次要潜在拮抗剂研究。两次保守的每日5 mg玻璃体内注射当前探针化合物导致Rod Opsin mRNA的25％抑制作用。但是，目前的探针化合物的效力太低，无法在四个星期内提供有效的眼内剂量的实验慢速释放公式，这是在许多ROD RP模型中抑制光感受器变性所需的持续时间。在AIM 1中，我们基于Orphagen开发的专有拮抗剂的3-D计算模型，从商业化合物库中鉴定出新的受体拮抗剂支架，以扩大后续医学化学的起点；在AIM 2中，我们进行了重点的医学化学，以提高效力，目的是在原发性视网膜培养物中实现IC50 <40 nm的ROD OPSIN抑制；在AIM 3中，我们选择具有提高效力和效率的铅化合物（ROD OPSIN mRNA抑制> 30％时，在1 mg/1 mg/玻璃体内注射时），并评估残留功能（由ERG确定）排除视网膜毒性。如果第1阶段的SBIR目标成功完成，我们计划在第2阶段中制定铅受体拮抗剂，以持续玻璃体内释放，并在RP的啮齿动物模型中进行有效性和安全性研究，这将证明启动这种新型药物以供临床使用开发。