Optimization of Iron Chelator Delivery System

描述(申请人提供)：这项申请寻求资金，以研究一种有希望的新方法，为一种典型地折磨贫困和被剥夺公民权的人口的孤儿疾病提供螯合疗法。每年，美国数以万计的非裔美国人和其他人以及数以万计的各种国际人口遭受输血铁超载的痛苦，这是世界上与金属有关的最常见的毒性，死亡率最高。拟议的脂质体包裹去铁胺螯合疗法不需要患者使用泵，而且对于世界各地数以千计的铁超载患者来说是负担得起的，对他们来说，目前挽救生命的螯合疗法往往既困难又/或超出他们的承受能力，这取决于他们有什么治疗选择(如果有)。对于接受慢性输血治疗的患者来说，铁的螯合是至关重要的。反复输血会产生有毒的铁，最明显的是会影响肝脏和心脏。输血相关的铁超载是各种输血依赖型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)。40多年来，用螯合剂去铁胺治疗已经被证明是有效的，是铁螯合治疗的“黄金标准”。然而，去铁胺会迅速渗透到尿液中，导致有效的铁螯合需要大量的铁。我们将确定脂质体包裹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)确定甘露糖化、阳离子和/或普通脂质体中的去铁胺是否是治疗铁超载的有效方法，以及2)确定脂质体中的去铁胺是否会导致心律失常、心电图改变和影响心功能。具体目标2：在28天的GLP毒理学研究中，确定我们的脂质体是否注意到了去铁胺的毒性。 公共卫生相关性：这项申请寻求资金，以研究一种有希望的新方法，为孤儿疾病提供螯合疗法。每年，美国数以万计的非裔美国人和其他人以及数以万计的各种国际人口遭受输血铁超载的痛苦，这是世界上与金属有关的最常见的毒性，死亡率最高。拟议的脂质体包裹去铁胺螯合疗法不需要患者使用泵，而且对于世界各地数以千计的铁超载患者来说是负担得起的，对他们来说，目前挽救生命的螯合疗法往往既困难又/或超出他们的承受能力，这取决于他们有什么治疗选择(如果有)。

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.