Methanobactin rapidly facilitates biliary copper excretion in a Wilson disease rat model visualised byCu PET/MRI.

Abstract

BACKGROUND AND PURPOSE: Methanobactins are peptides with high copper affinity and potential to treat Wilson disease. We examined how two methanobactins (ARBM101 and MB-OB3b) affected copper handling in the LPP Atp7bWilson disease rat model, compared to penicillamine or saline, byCu positron emission tomography/magnetic resonance imaging. Heterozygotes served as controls. EXPERIMENTAL APPROACH: Cu was administered i.v. to 19 LPP and four control rats. A baseline scan was performed 1 h later. LPP rats received one dose of saline, penicillamine, MB-OB3b or ARBM101 i.p. (t = 100 min), followed by a 90-min scan and a final scan at t = 24 h. Controls followed identical procedures without intervention.Cu levels were evaluated as % injected dose (%ID) in the liver, kidney and 'abdominal-pelvic region' (intestines and other non-hepatic, non-renal organs). KEY RESULTS: At baseline, hepatic %ID was ≈50% higher in LPP rats than in controls. IntraintestinalCu activity, indicating biliary excretion, was present in controls and absent in LPP rats. After methanobactin injection (but not saline or penicillamine),Cu appeared in the small intestines of LPP rats within 10-15 min. Hepatic %ID increased over 24 h in saline-, penicillamine- and MB-OB3b-injected rats but decreased in control rats. ARBM101 almost normalised hepaticCu at 24 h. CONCLUSIONS AND IMPLICATIONS: A single i.p. methanobactin dose restored biliary copper excretion in LPP rats. The effect was more pronounced with ARBM101 than with MB-OB3b. Non-ATP7B transporters must be involved because ATP7B is absent in LPP rats. Methanobactin may have therapeutic potential in Wilson disease.