Sarcoidosis is a systemic disease with large unmet medical need, and unknown cause, characterized by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system. About 30% of patients develop a chronic or progressive disease necessitating long-term treatment. Current therapies ? including the standard of care, systemic corticosteroids ? do not prolong survival and only have limited, short- term benefits, with significant side-effects. Mortality, estimated to occur in up to 8% of patients, is mainly due to respiratory failure, with pulmonary fibrosis a common feature. The overall objective of this project is for OncoArendi Therapeutics (OAT) to develop an oral, small molecule chitotriosidase 1 (CHIT1) inhibitor as a 1st-in-class medicine for sarcoidosis, with superior clinical benefit and safety compared to current treatments. CHIT1 is one of two enzymatically active chitinases, which have been implicated in several disorders, including interstitial lung diseases (ILDs) such as sarcoidosis. Studies have demonstrated elevated levels (>10-fold) of CHIT1 in serum and bronchoalveolar lavage fluid (BALF) of sarcoidosis patients, which correlated with disease severity. In preliminary studies we have confirmed the reports of increased serum CHIT1 levels in sarcoidosis patients. We have identified proprietary potent and selective oral small molecule inhibitors of CHIT1, such as OAT-2068. The specific goals of this application are: evaluation of the effects of a potent and selective CHIT1 inhibitor, OAT-2068, in the beryllium-induced murine model of granulomatous lung disease (Aim 1) and investigation of the levels of CHIT1 in patients with sarcoidosis and evaluation of the role of CHIT1 in the granuloma formation ex vivo (Aim 2).
For Aim 1, as the pathologies of sarcoidosis and chronic beryllium disease (CBD) are indistinguishable, and there are no models of sarcoidosis, a model of CBD will be used. Specifically, the effects of oral OAT-2068 (30 mg/kg), a potent and selective CHIT inhibitor, will be examined in a humanized mouse model of CBD involving challenge of HLA-DP2 transgenic animals to beryllium oxide (BeO). The following endpoints will be measured: i) granulomatous inflammation burden in lungs; ii) CD4+ cell counts in BALF; iii) Be-specific T cells in lungs and spleen; iv) lung fibrosis; v) CHIT1 expression in lungs; (vi) the pharmacodynamic effects of OAT-2068 will be determined by measuring chitinolytic activity in serum and BAL.
For Aim 2, the levels and cellular origins of CHIT1 will be investigated in the BALF and serum from up to 25 patients with sarcoidosis and 20 age-matched controls, using standard enzymatic (chitinolytic activity) techniques. An ex vivo model of multi-cellular granuloma formation using human BALF cells from sarcoidosis patients will be utilized to measure CHIT1 expression. Successful completion of the studies in this proposal will lay the foundation for the future development of an orally active selective CHIT1 inhibitor, which is expected to have improved efficacy, safety and tolerability compared to current medicines for sarcoidosis.
Chronic and progressive sarcoidosis is a serious systemic disease with significant mortality, that affects various organs, including the lungs, and for which there is no cure or effective medicines. We are performing research, including the use of disease- relevant animal models and blood and lung cells from sarcoidosis patients, on a new type of oral drug (a chitinase inhibitor) that has the potential to provide superior medical benefit and improved safety compared to current treatments, and will increase survival and the quality of life for people with sarcoidosis. The results from the studies outlined in this application will be an important step towards the clinical testing of chitinase inhibitors in sarcoidosis patients.