Optimization of Iron Chelator Delivery System

描述（由申请人提供）：本申请寻求资金，以调查一种有前途的新方法，为一类孤儿疾病提供螯合治疗，这些疾病通常困扰贫困和被剥夺权利的人群。在美国，成千上万的非洲裔美国人和其他人以及成千上万的各种国际人群每年遭受输血铁过载，这是世界上最常见的金属相关毒性，死亡率最高。所提出的脂质体包埋的去铁胺螯合治疗将不需要患者使用泵，并且对于全世界成千上万的铁超负荷患者来说是负担得起的，对于这些患者来说，目前挽救生命的螯合治疗通常仍然是困难的和/或他们在金钱上无法获得的，这取决于他们存在什么样的治疗选择（如果有的话）。铁螯合对接受慢性输血治疗的患者至关重要。反复输血会产生毒性水平的铁，最明显的是影响肝脏和心脏。输血相关的铁超负荷是各种输血依赖性贫血患者发病和死亡的主要原因，包括镰状细胞性贫血和重型地中海贫血（库利氏贫血）。使用螯合剂去铁胺治疗已被证明有效超过40年，是铁螯合治疗的“金标准”。然而，去铁胺被迅速过滤到尿液中，导致需要大量的有效铁螯合。我们将确定脂质体包埋的去铁胺是否具有作为靶向递送系统的潜力。我们的具体目标是：具体目标1：1）确定包埋在甘露糖基化、阳离子和/或普通脂质体中的去铁胺是否是铁过载的有效治疗，和2）确定包埋在脂质体中的去铁胺是否引起心律失常、心电图变化和影响心脏功能。具体目标2：确定在28天GLP毒理学研究期间，我们的脂质体包封的去铁胺是否观察到毒性。 公共卫生相关性：该申请寻求资金，以研究一种有前途的新方法，为孤儿疾病提供螯合治疗。在美国，成千上万的非洲裔美国人和其他人以及成千上万的各种国际人群每年遭受输血铁过载，这是世界上最常见的金属相关毒性，死亡率最高。所提出的脂质体包埋的去铁胺螯合治疗将不需要患者使用泵，并且对于全世界成千上万的铁超负荷患者来说将是可负担的，对于这些患者来说，目前的挽救生命的螯合治疗通常仍然是困难的和/或他们在金钱上负担不起的，这取决于他们存在什么样的治疗选择（如果有的话）。

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.