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。主要的生化 STGD1缺陷是在视网膜色素上皮中过度形成了细胞毒性脂肪蛋白双膜素双膜素 （RPE）由于ABCA4基因中的隐性突变。没有针对星巴特疾病的治疗方法。专业 RPE脂肪霉素的细胞毒性成分是吡啶双蛋白素，形成为副产物 视力类维生素周期。有人提出，视觉周期的部分抑制可能会减少 脂肪霉素双蛋白素，并在Stargardt疾病中延长RPE和感光体存活。关键的一步 视觉周期是通过称为酶的全反式返回酯转化为11-CIS-返里醇 异素水解酶（IMH）。已经显示RPE65代表IMH，它从 RPE中的全反视网膜酯。 IMH反应在视觉周期函数中是限制的，因此使 RPE65视觉周期抑制的重要药物靶标。视觉周期的药理阻塞 通过RPE65抑制作用可有效地减少ABCA4 - / - 小鼠中的双蛋白素产生 Stargardt疾病的模型。但是，直接RPE65作为治疗策略的抑制作用是复杂的 基于机制的不良反应（AES）的严重程度，选择性RPE65抑制剂不可能是 由于其过度的视网膜毒性，在临床上以有效剂量使用。为了降低RPE65的水平 抑制与AE相关的阈值以下，同时保持降低双性素的功效，我们将 开发一类新型的双特异性化合物，除了RPE65抑制作用外，这些化合物还将充当视网膜甲醛 陷阱。视网膜醛是直接双素的前体，其中和通过形成 可逆的Schiff碱或1,3-恶阵加合物使用含胺或氨基甲醇的化合物， 分别将减少双肾上腺素的合成。双特异性化合物的使用将允许降低水平 在与AES相关的阈值以下的RPE65的抑制 功效。两种新型非类素化合物RPE65-61和RPE65-71将作为起点 在与特定目标相关的研究中，新型双特异性药物的药物化学优化1。 传统的眼科药效标记与抑制视觉周期和抑制有关 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IN 双特异性化合物的体内活性，并选择安全但有效剂量的范围（特定目标2）。 评估体内功效以及评估慢性剂量后的视网膜毒性评估 在Stargardt疾病的小鼠遗传模型中（特定目标3）。