Retinoic Acid Modulation for Scleroderma

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、慢性的自身免疫性结缔组织疾病，主要导致皮肤增厚和硬化，以及肺、胃肠道和动脉的间质纤维化。据估计，SSc在美国的患病率为每百万140至276例（或49000至90000例），使其成为一种罕见疾病。针对SSc的药物已获得FDA的孤儿药地位。全反式维甲酸（ATRA）是维生素A最活跃的代谢物，在几种系统性硬化症的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，CYP26是负责ATRA代谢的关键酶。Angion已经确定了一个有前途的专利系列有效和选择性的小分子CYP26抑制剂具有优异的药物样特性。Angion已经证明CYP26抑制剂可以维持血清ATRA水平的生理增加，并且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和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于视黄酸信号通路的慢性调节，这可能是治疗SSc所需要的。目前的建议是评估我们的CYP26抑制剂是否在SSc的临床前动物模型中显示活性。因此，我们的目标是产生关键的概念证明数据，可以保证CYP26抑制剂用于孤儿适应症SSc的进一步临床前和临床开发。

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.