A major problem in the treatment of patients who require chronic red cell transfusion results from the cellular oxidative toxicity of iron. Some improvements may be made in technologies from removal of iron from patients through simple extension of existing methods of chelation. However, major advances may require the development of fundamentally different approaches to therapy. The applicants propose work which will both extend existing therapeutic modalities and lead to the development of novel types of therapy. There include: (1) The further development of new high molecular weight derivatives of desferrioxamine, with the aim of conducting tests within 18 months of the inception of this grant. These agents will be tested in cellular, animal and human models of iron overload. (2) The design of new combination chelators based upon the use of two agents, a membrane permeating 'metalophore' which will form a relatively low affinity lipophilic iron chelate and a high affinity (extracellular) hydrophilic agent which will bind the iron as it is extruded by the metalophore. (3) Investigation of the mechanisms underlying iron-induced erythrocyte oxidant damage in thalassemia (mouse and human) and development of antioxidant and chelation strategies for the prevention of such damage and improvement of red cell viability. They plan to use a well characterized thalassemic mouse as a model to test new chelators, combination of chelators and new antioxidants. Results from studies in the mouse will be used to develop strategies to be tested in non-transfused (Hb)E thalassemic patients and then in chronically transfused patients. A number of new laboratory methods will be used to assess oxidative damage and evaluate antioxidant and chelation interventions. If successful, this approach would diminish the transfusion requirement and iron accumulation. (4) Development of implantable and more tractable systems for constant delivery of chelating agents and testing of both the chelating and antioxidant modalities developed as a result of this work. (5) Application of proven elements from these four components to patients with transfusion induced iron overload (beta thal major, E/beta thal, sickle cell).
|Scott, M D; van den Berg, J J; Repka, T et al. (1993) Effect of excess alpha-hemoglobin chains on cellular and membrane oxidation in model beta-thalassemic erythrocytes. J Clin Invest 91:1706-12|
|Scott, M D; Rouyer-Fessard, P; Ba, M S et al. (1992) Alpha- and beta-haemoglobin chain induced changes in normal erythrocyte deformability: comparison to beta thalassaemia intermedia and Hb H disease. Br J Haematol 80:519-26|
|Scott, M D (1992) Entrapment of purified alpha-hemoglobin chains in normal erythrocytes as a model for human beta thalassemia. Adv Exp Med Biol 326:139-48|