Circulating Anandamide is an Early Blood Biomarker of Progressive Hermansky-Pudlak Syndrome Pulmonary Fibrosis

Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS-1, leads to fatal adult-onset pulmonary fibrosis (PF) with no effective treatment. Endocannabinoid/cannabinoid receptor 1 (CB1R) overactivity promotes fibrogenesis in lungs, and peripheral CB1R antagonism provided therapeutic benefit in bleomycin induced-PF mouse models of IPF and HPSPF. We investigated whether endocannabinoids could serve as blood biomarkers of PF in HPS. In three separate cohorts, circulating AEA levels were increased in HPS-1 patients with or without PF, compared to healthy volunteers. Circulating AEA levels were negatively correlated with PFT. A longitudinal study over the course of 5-14 years with HPS-1 patients indicated that circulating AEA levels begin to increase with the fibrotic lung process even at the subclinical stages of HPSPF. Similar to the HPS-1 and HPSPF patients, serum AEA levels were significantly increased in the mouse model of bleomycin-induced HPSPF in the earliest stages of PF and remained elevated at a later fibrotic stage. Zevaquenabant (MRI-1867), a peripheral CB1R and iNOS antagonist, was identified as a candidate drug to treat patients with HPSPF with its superior anti-fibrotic efficacy and is being tested in phase 1 clinical trial. Importantly, Zevaquenabant administration starting at day 8 post bleomycin completely reversed elevated circulating AEA levels in pale ear mice and halted progression of fibrosis, suggesting its target engagement, inhibition of the CB1R system and therapeutic efficacy. In conclusion, circulating AEA may be a prognostic blood biomarker for PF in HPS-1 patients.