SBIR-STTR Award

Organ failure due to iron-mediated injury is the leading cause of death in patients with disorders such as thalassemia major that require long-term chronic transfusion. Treatment with the iron chelator, Desferrioxamine, can prevent iron-related morbidity and mortality. Most patients use Desferrioxamine suboptimally, however, due largely to its unwieldy mode of administration, namely continuous subcutaneous infusion over 12 to 24 hours. The investigators will explore the feasibility of using new delivery systems for the drug. Drug delivery will be targeted to the heart and liver, the organs most susceptible to iron-mediated injury. Initial studies of toxicity and efficacy of delivery will be carried out using a rat model system. The concentration of Desferrioxamine will approximate, that needed for clinical efficacy. Subsequent experiments will be performed with iron overloaded thalassemic rats, as well as iron overloaded pigs. This work should lead to an efficacious mode of chelation therapy that is acceptable to patients. In addition, the new delivery method could be used in countries that presently lack the capital resources for the standard Desferrioxamine administration. PROPOSED COMMERCIAL APPLICATION: Alternative approaches to iron chelation therapy and enhancement of targeted drug delivery are of great commercial value. By improving biological half life, tissue targeting ease of administration will result in cost reduction to patients receiving the iron-chelation therapy. The two compounds currently used present a number of clinical problems

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.

Public Health Relevance:
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