Methanobactin rapidly facilitates biliary copper excretion in a Wilson disease rat model visualised by 64Cu 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 Atp7b^-/- Wilson disease rat model, compared to penicillamine or saline, by ⁶⁴Cu positron emission tomography/magnetic resonance imaging. Heterozygotes served as controls.

Experimental approach: ⁶⁴Cu 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. ⁶⁴Cu 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. Intraintestinal ⁶⁴Cu activity, indicating biliary excretion, was present in controls and absent in LPP rats. After methanobactin injection (but not saline or penicillamine), ⁶⁴Cu 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 hepatic ⁶⁴Cu 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.