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的缺陷是在视网膜色素上皮中过度形成细胞毒性脂褐素双维A酸 (RPE)是由于ABCA4基因的隐性突变。目前还没有治疗斯塔加特病的方法。少校 RPE脂褐素的细胞毒性成分是双维A酸吡啶，它是由 视觉维甲酸循环。有人认为，部分抑制视觉周期可能会减少视觉周期的形成 脂褐素、双维甲酸和延长Stargardt病的RPE和光感受器存活。迈出的关键一步 视觉循环是全反式视黄酸酯转化为11-顺式视黄醇的酶，称为 异构酶(IMH)。已经证明，RPE65代表IMH，它从 RPE中的全反式视黄酸酯。IMH反应在视觉循环功能中是限速的，因此使 RPE65是抑制视觉周期的重要药物靶点。视觉周期的药理障碍 通过抑制RPE65被证明有效地减少ABCA4-/-小鼠中双维A酸的产生 Stargardt病模型。然而，直接抑制RPE65作为一种治疗策略是复杂的 基于机制的不良反应(AEs)的严重性，而且选择性RPE65抑制剂不太可能 由于其过度的视网膜毒性，临床上使用有效剂量。为了降低RPE65的水平 抑制低于阈值与血管紧张素转换酶相关，同时保持双维A酸类药物的降低效果，我们将 开发一类新型的双功能化合物，除了RPE65抑制外，它还将作为视黄醛 陷阱。视黄醛是直接的双维A酸类前体，它们通过形成 使用伯胺或含氨基卡宾的化合物的可逆希夫碱或1，3-恶嗪加合物， 都会减少双维A酸的合成。双功能化合物的使用将允许降低水平 RPE65抑制低于与AEs相关的阈值，同时维持双维A类药物的联合降低 功效。两种新的非维甲酸化合物RPE65-61和RPE65-71将作为 药物化学优化新类双功能药物在相关研究中的具体目标1。 传统的眼部药效学标志物与抑制视觉周期和抑制 Rod ERG信号和一种与醛捕获相关的新的血清生物标记物将用于证明在 研究双功能化合物的体内活性，并选择安全有效的剂量范围(具体目标2)。 将进行体内疗效的评估以及长期给药后的视网膜毒性评估 在Stargardt病的小鼠遗传模型中(特异性目标3)。