Retinoic Acid Modulation for Scleroderma

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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.