Polypharmacological approach to treatment of Stargardt disease

治疗 Stargardt 病的多药理学方法

• 批准号: 10561110
• 负责人: Christopher L. Cioffi
• 金额: $ 64.51万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561110
• 关键词: 11-cis-Retinol; Ablation; Adverse effects; Adverse event; Aldehydes; Alleles; Amines; Amino Acid Substitution; Applications Grants; Biochemical; Biochemical Pathway; Biological Availability; Biological Markers; Blood; Characteristics; Chronic; Clinical; Clinical Trials; Defect; Disease; Dose; Drug Kinetics; Drug Targeting; Enzymes; Equilibrium; Esters; Evaluation; Excretory function; Frequencies; Future; General Population; Genes; Genetic; Genetic Models; Goals; Heterozygote; Human; In Vitro; Inherited; Lipofuscin; Macular degeneration; Metabolism; Mouse Strains; Mus; Mutation; Nonexudative age-related macular degeneration; Oral; Pathologic; Patients; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phase; Photoreceptors; Prevalence; Production; Property; RPE65 protein; Reaction; Retina; Retinaldehyde; Retinoids; Rod; Safety; Schiff Bases; Series; Serum; Severities; Signal Transduction; Specificity; Stargardt' s disease; Structure of retinal pigment epithelium; Testing; Therapeutic; Treatment Efficacy; Vision; Visual; absorption; adduct; analog; antagonist; clinical efficacy; cytotoxic; design; experimental study; improved; in vivo; in vivo evaluation; inhibitor; macular dystrophy; mouse genetics; mouse model; mutant; novel; pharmacodynamic biomarker; pharmacologic; pre-clinical; preclinical efficacy; response; retinal toxicity; small molecule; treatment strategy; visual cycle

Stargardt disease (STGD1) is the most common form of inherited macular dystrophy. The primary biochemical defect in STGD1 is excessive formation of cytotoxic lipofuscin bisretinoids in the retinal pigment epithelium (RPE) due to recessive mutations in the ABCA4 gene. There is no treatment for Stargardt disease. The major cytotoxic components of RPE lipofuscin are pyridinium bisretinoids, which are formed as by-products of the visual retinoid cycle. It was suggested that partial inhibition of the visual cycle may reduce the formation of lipofuscin bisretinoids and prolong the RPE and photoreceptor survival in Stargardt disease. A critical step in the visual cycle is the conversion of all-trans-retinyl ester to 11-cis-retinol by the enzyme called isomerohydrolase (IMH). It has been shown that RPE65 represents IMH, which produces 11-cis-retinol from all-trans-retinyl ester in the RPE. The IMH reaction is rate-limiting in the visual cycle function thus making RPE65 an important drug target for the visual cycle inhibition. Pharmacological blockage of the visual cycle accomplished by RPE65 inhibition was shown to effectively reduce bisretinoid production in the Abca4-/- mouse model of Stargardt disease. However, direct RPE65 inhibition as a therapeutic strategy is complicated by the severity of mechanism-based adverse effects (AEs), and it is unlikely that selective RPE65 inhibitors can be used clinically at efficacious doses due to their excessive retinal toxicity. In order to reduce the levels of RPE65 inhibition below the threshold associated with AEs while maintaining a bisretinoid-lowering efficacy, we will develop a class of novel bispecific compounds which in addition to RPE65 inhibition will act as retinaldehyde traps. Retinaldehydes are direct bisretinoid precursors, and their neutralization through the formation of reversible Schiff base or 1,3-oxazinane adducts using primary amine- or aminocarbinol-containing compounds, respectively, would reduce bisretinoid synthesis. The use of bispecific compounds will allow to reduce the level of RPE65 inhibition below the threshold associated with AEs while maintaining a combined bisretinoid-lowering efficacy. Two novel non-retinoid compounds, RPE65-61 and RPE65-71, will serve as the starting points in medicinal chemistry optimization of the new class of bispecific agents in studies related to Specific Aim 1. Traditional ocular pharmacodynamic markers related to the inhibition of the visual cycle and suppression of the rod ERG signal along with a new serum biomarker related to aldehyde trapping will be used to prove the in vivo activity of bispecific compounds and to select the range of safe yet efficacious doses (Specific Aim 2). Evaluation of in vivo efficacy along with the assessment of retinal toxicity after chronic dosing will be conducted in the mouse genetic models of Stargardt disease (Specific Aim 3).

Stargardt 病 (STGD1) 是遗传性黄斑营养不良的最常见形式。初级生化 STGD1 的缺陷是视网膜色素上皮中细胞毒性脂褐质双视黄醇的过度形成 (RPE) 由于 ABCA4 基因隐性突变。斯塔加特病没有治疗方法。主要 RPE 脂褐素的细胞毒性成分是吡啶鎓双维A酸，它是作为脂褐质的副产物形成的。 视觉类维生素A循环。有人提出，部分抑制视觉周期可能会减少视觉循环的形成 脂褐素双视黄醇并延长 Stargardt 病中 RPE 和光感受器的存活。关键的一步 视觉循环是通过称为 11-顺式-视黄醇的酶将全反式视黄酯转化为 11-顺式视黄醇 异构水解酶（IMH）。研究表明，RPE65 代表 IMH，可产生 11-顺式视黄醇 RPE 中的全反式视黄酯。 IMH 反应在视觉循环功能中是限速的，因此使得 RPE65 是视觉周期抑制的重要药物靶点。视觉循环的药理学阻断 通过 RPE65 抑制实现的结果显示可有效减少 Abca4-/- 小鼠中双维A酸的产生 Stargardt 病模型。然而，直接抑制 RPE65 作为一种治疗策略因以下因素而变得复杂： 基于机制的不良反应 (AE) 的严重程度，并且选择性 RPE65 抑制剂不太可能 由于其过度的视网膜毒性，临床上以有效剂量使用。为了降低RPE65的水平 抑制低于与 AE 相关的阈值，同时保持双维A酸降低功效，我们将 开发一类新型双特异性化合物，除了抑制 RPE65 之外，还可以起到视黄醛的作用 陷阱。视黄醛是直接的双视黄醇前体，它们通过形成 使用含有伯胺或氨基甲醇的化合物的可逆希夫碱或1,3-恶嗪烷加合物， 分别会减少双维A酸的合成。双特异性化合物的使用将允许降低水平 RPE65 抑制低于与 AE 相关的阈值，同时维持联合双维A酸降低 功效。两种新型非类视黄醇化合物 RPE65-61 和 RPE65-71 将作为研究的起点 与特定目标 1 相关的研究中新型双特异性药物的药物化学优化。 与视觉周期抑制和视觉抑制相关的传统眼部药效学标志物 杆 ERG 信号以及与醛捕获相关的新血清生物标志物将用于证明 双特异性化合物的体内活性并选择安全有效的剂量范围（具体目标 2）。 将进行体内疗效评估以及长期给药后视网膜毒性评估 在 Stargardt 病小鼠遗传模型中（具体目标 3）。