IRON CLEARANCE BY TRANSFERRIN HALF-MOLECULES

THE HYPOTHESIS TO BE TESTED IS THAT THE 40 KDA, HALF-MOLECULES OF TRANSFERRIN ARE CAPABLE OF BINDING EXCESS IRON IN PARENCHYMALLY OR RETICULOENDOTHELIALLY IRON OVERLOADED LIVER CELLS IN CULTURE AND IN MICE AND ELIMINATING THIS BOUND IRON INTO THE MEDIUM OR VIA THE KIDNEY. HUMAN OR RAT HEPATOMA CELLS IN CULTURE WILL BE IRON LOADED. THE RELATIVE EFFICIENCIES OF IRON REMOVAL FROM THESE CELLS BY (A) DEFEROXAMINE, (B) HOLOAPOTRANSFERRINS AND (C) APOTRANSFERRIN HALF-MOLECULES SEPARATELY AND IN COMBINATION, WILL BE COMPARED. ADULT MICE WILL BE IRON LOADED BY HYPERTRANSFUSION OR BY FEEDING A HIGH IRON DIET. THE RELATIVE EFFICIENCIES OF IRON CLEARANCE IN NORMAL, HYPERTRANSFUSED AND DIETARILY IRON LOADED MICE IN (A) NON-TREATED CONTROLS, (B) ANIMALS INFUSED WITH DEFERRIOXAMINE AND (C) ANIMALS INFUSED WITH VARIOUS APOTRANSFERRIN HALF-MOLECULES, WILL BE COMPARED. THE POTENTIAL FOR TECHNOLOGICAL INNOVATION AND COMMERCIAL APPLICATION IN PHASE II WOULD BE THE DEVELOPMENT OF A "SYNTHETIC ORGAN" FOR IMPLANTATION IN PERSONS WITH ONGOING TRANSFUSIONAL IRON OVERLOAD E. G., THALASSEMICS. THIS ORGAN WOULD BE DESIGNED, TO PRODUCE FROM BODY FLUIDS, A STEADY SUPPLY OF RECOMBINANT HUMAN TRANSFERRIN HALF-MOLECULE(S) FOR BINDING EXCESS IRON AND EXCRETING IT IN THE URINE.