Pharmacological Suppression of Rod Opsin as Therapy for Retinitis Pigmentosa

描述（由申请人提供）：色素性视网膜炎（RP）是一种影响100,000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。目前还没有批准的治疗该疾病的方法，而基因治疗虽然有希望，但由于潜在基因突变的多样性而受到限制。视杆蛋白是光感受器外段高表达的主要蛋白成分，其异常定位一直被认为是RP动物模型中光感受器细胞死亡前的一个主要事件。最近，在两种纤毛病小鼠模型中，通过遗传方法减少视蛋白杆表达可显著延缓视网膜外核层光感受器的快速丧失。Orphagen已经发现了一种特异性的小分子配体，这种小分子配体是一种以前未被发现的孤儿受体，它在光感受器层中表达，对早期视网膜发育至关重要。在初代新生大鼠视网膜培养中，该受体的拮抗剂（IC50 < 250 nM）以受体特异性的方式部分抑制视蛋白的表达。在大鼠玻璃体内注射后，我们目前的探针化合物也显著抑制杆视蛋白mRNA。研究结果表明，同一受体的临床拮抗剂将降低40%的视杆蛋白定位错误是视杆细胞死亡因素的RP患者的光感受器变性率。为了响应PAR-09-260，神经系统小分子探针的优化，我们建议鉴定一种更有效的拮抗剂，这是体内原理证明所必需的

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.