Retinoic Acid Modulation for Scleroderma
视黄酸调节硬皮病
基本信息
- 批准号:8353140
- 负责人:
- 金额:$ 29.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-01 至 2013-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAdultAnimal ModelArteriesAutoimmune ProcessBiochemicalBiological AvailabilityBleomycinCaringChemicalsChronicClinicalClinical TreatmentClinical TrialsCollagenComplexConnective Tissue DiseasesCytochrome P450DataDependenceDermalDevelopmentDiffuse SclerodermaDiseaseDoseDrug Delivery SystemsEnzymesEvaluationEvaluation ResearchExhibitsFibrosisGastrointestinal tract structureGeneticGoalsGrantIn VitroLeadLiverLiver FibrosisLungMetabolismModelingMorbidity - disease rateMusOralOrphanOrphan DrugsPatientsPharmaceutical PreparationsPhasePhysiologicalPre-Clinical ModelPrevalencePropertyRandomizedRare DiseasesSafetySclerodermaSeriesSerumSignal PathwaySignal TransductionSkinSmall Business Innovation Research GrantSystemic SclerodermaTherapeuticToxicologyTreatment EfficacyTretinoinUnited StatesVitamin Aadenosine deaminasedrug developmenteffective therapyin vivoinhibitor/antagonistinterstitialmortalityphase 2 studypre-clinicalprogramssmall moleculesocioeconomics
项目摘要
DESCRIPTION (provided by applicant): Systemic sclerosis (SSc) or diffuse scleroderma is a complex, chronic, autoimmune, connective tissue disease which primarily causes skin thickening and hardening in addition to interstitial fibrosis of lungs, gastrointestinal tract and arteries. Estimates of the prevalence of SSc in the United States (US) range from 140 to 276 patients per million (or 49,000 to 90,000 patients) making it a rare disease. Drugs targeting SSc have received Orphan Drug Status from the FDA. All-trans-retinoic acid (ATRA) is the most active metabolite of vitamin A and has been shown to have antifibrotic properties in several preclinical models of systemic sclerosis. Endogenous ATRA levels can be modulated by inhibition of the Cytochrome P450 CYP26, the key enzyme responsible for ATRA metabolism. Angion has identified a promising proprietary series of potent and selective small molecule CYP26 inhibitors with excellent drug-like properties. Angion has shown that CYP26 inhibitors can sustain physiological increases in serum ATRA levels and that they are antifibrotic in preclinical animal models of lung and liver fibrosis. The excellent oral systemic bioavailability and the possibility of sustained modulation of ATRA in a physiological range make our compounds eminently suitable for chronic modulation of retinoic acid signaling pathways, as likely required for the therapy of SSc. The current proposal is to evaluate whether our lead CYP26 inhibitors show activity in preclinical animal models of SSc. We thus aim to generate critical proof of concept data that could warrant the further preclinical and clinical development of CYP26 inhibitors for the orphan indication SSc.
PUBLIC HEALTH RELEVANCE: Systemic sclerosis (SSc) or diffuse scleroderma is a rare fibrotic disease without effective therapy. Angion has identified a promising new series of modulators of retinoic acid signaling and shown that such compounds have anti-fibrotic activity in models of liver and lung fibrosis. We propose here to also evaluate their activity in preclinica animal models of SSc. We thus aim to generate critical proof of concept data that could warrant their further preclinical and clinical development for SSc.
描述(由申请人提供):系统性硬化症(SSc)或弥漫性硬皮病是一种复杂的慢性自身免疫性结缔组织疾病,除了肺、胃肠道和动脉间质纤维化外,主要导致皮肤增厚和硬化。据估计,美国 (US) 的 SSc 患病率范围为每百万人 140 至 276 名患者(或 49,000 至 90,000 名患者),使其成为一种罕见疾病。针对 SSc 的药物已获得 FDA 的孤儿药资格。全反式视黄酸 (ATRA) 是维生素 A 最活跃的代谢物,在多种系统性硬化症临床前模型中已被证明具有抗纤维化特性。内源性 ATRA 水平可以通过抑制细胞色素 P450 CYP26 来调节,细胞色素 P450 CYP26 是负责 ATRA 代谢的关键酶。 Angion 已经确定了一系列有前途的专有强效选择性小分子 CYP26 抑制剂,具有优异的药物样特性。 Angion 已表明 CYP26 抑制剂可以维持血清 ATRA 水平的生理性增加,并且它们在肺和肝纤维化的临床前动物模型中具有抗纤维化作用。优异的口服全身生物利用度以及在生理范围内持续调节 ATRA 的可能性使我们的化合物非常适合长期调节视黄酸信号通路,这可能是治疗 SSc 所需的。目前的提议是评估我们的主要 CYP26 抑制剂是否在 SSc 临床前动物模型中显示出活性。因此,我们的目标是生成关键的概念验证数据,以保证针对孤儿适应症 SSc 的 CYP26 抑制剂的进一步临床前和临床开发。
公共卫生相关性:系统性硬化症 (SSc) 或弥漫性硬皮病是一种罕见的纤维化疾病,没有有效的治疗方法。 Angion 发现了一系列有前景的新型视黄酸信号调节剂,并表明此类化合物在肝和肺纤维化模型中具有抗纤维化活性。我们在此建议也评估它们在 SSc 临床前动物模型中的活性。因此,我们的目标是生成关键的概念验证数据,以保证 SSc 的进一步临床前和临床开发。
项目成果
期刊论文数量(0)
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Bert J. W. M. Oehlen其他文献
Bert J. W. M. Oehlen的其他文献
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