Optimization of Iron Chelator Delivery System

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DESCRIPTION (provided by applicant): This application seeks funding to investigate a promising and novel approach to provide chelation therapy for a category of orphan diseases which typically afflict impoverished and disenfranchised populations. Tens of thousands of African Americans and others in the United States, as well as tens of thousands of various international populations suffer each year from transfusional iron overload, which is the most common metal-related toxicity with the highest mortality rate in the world. The proposed liposome-entrapped Desferrioxamine chelation treatment would not require patients to use a pump and would be affordable for the thousands of iron-overload sufferers throughout the world for whom current life-saving chelation treatment often remains both a hardship and/or out of their reach monetarily depending on what treatment options, if any, exist for them. Iron chelation is vital to patients who receive chronic transfusion therapy. Repeated transfusions produce toxic levels of iron that affect, most notably, the liver and heart. Transfusion related iron overload is a major cause of morbidity and mortality in patients with a variety of transfusion-dependent anemias, including sickle cell anemia and thalassemia major (Cooley's anemia). Treatment with the chelator, Desferrioxamine, has been proven effective for over 40 years and is the "gold standard" in iron chelation therapy. However, Desferrioxamine is rapidly filtered into the urine resulting in large amounts being needed for effective iron chelation. We will determine whether liposome-entrapped Desferrioxamine holds potential as a targeted delivery system. Our specific aims are: Specific Aim 1: 1) Determine whether Desferrioxamine entrapped in either mannosylated, cationic and/or plain liposomes is an effective treatment for iron overload and 2) Determine if Desferrioxamine entrapped in liposomes cause arrhythmias, changes in the electrocardiogram, and impacts cardiac function. Specific Aim 2: Determine if toxicity is noted with our liposome entrapped Desferrioxamine during 28-day GLP toxicology studies. PUBLIC HEALTH RELEVANCE: This application seeks funding to investigate a promising and novel approach to provide chelation therapy for orphan diseases. Tens of thousands of African Americans and others in the United States, as well as tens of thousands of various international populations suffer each year from transfusional iron overload, which is the most common metal-related toxicity with the highest mortality rate in the world. The proposed liposome- entrapped Desferrioxamine chelation treatment would not require patients to use a pump and would be affordable for the thousands of iron-overload sufferers throughout the world for whom current life-saving chelation treatment often remains both a hardship and/or out of their reach monetarily depending on what treatment options, if any, exist for them.