Twice-Weekly Subcutaneous Liposome Chelator to Treat Transfusional Iron Overload

描述（由申请人提供）：每年约有10万名婴儿出生时患有严重的地中海贫血型血液疾病或镰状细胞性贫血，导致终身输血。然而，身体不能有效地去除铁，因此输血中的额外铁积累。这会导致血液中的毒性积聚，肝脏和脾脏中的铁储存蛋白饱和，导致铁诱导的肝脏疾病，内分泌失调和心肌病。如果不及时治疗，铁诱导的心肌病不可避免地导致死亡，在孩子成年之前。输血铁超载可以通过螯合治疗。批准的铁螯合剂遭受严重的缺点，我们的目标是克服有针对性的螯合剂输送策略。我们设计了一种新型的、稳定的纳米脂质体（LDFO）制剂，其含有高浓度的铁螯合剂去铁胺（DFO）。我们将检验新LDFO皮下（SC）给药导致肝脏和脾脏中治疗性DFO浓度和血液中DFO持续水平的假设。将完成三个具体目标：在目标1中，我们将优化Liposomal-DFO制剂。在目标2中，我们将确定脂质体DFO制剂的储存稳定性。在目标3中，我们将确定当通过静脉内和皮下途径给药时脂质体DFO的药代动力学和生物分布特征。这种将DFO靶向递送至体内主要铁储存部位将比输注DFO更有效地从深部组织部位去除铁。 未包封的DFO将在当前输注时间的1/40内输注当前使用的DFO剂量的1/8。该制剂比Desferal（R）更容易和更安全。如果LDFO得到验证，这将是一个重大的进步，在儿科患者的输血铁超载的临床治疗。

DESCRIPTION (provided by applicant): About 100,000 babies are born each year with severe thalassemia type blood disorders or sickle cell anemia, leading to a lifelong regime of blood transfusions. However, the body cannot efficiently remove iron hence the extra iron in the transfused blood accumulates. This causes a toxic build up in the blood, saturation of the iron storage proteins in the liver and spleen leading to iron-induced liver disease, endocrine disorders and cardiomyopathy. If left untreated, iron induced cardiomyopathy inevitably leads to death, before the child reaches adulthood. Transfusional iron overload can be treated by chelation. Approved iron chelators suffer from severe drawbacks that we aim to overcome with a targeted chelator delivery strategy. We have devised a novel, stable nanoliposome (LDFO) formulation containing a high concentration of the iron chelator desferroxamine (DFO). We will test the hypothesis that the subcutaneous (SC) administration of the novel LDFO results in a therapeutic DFO concentration in the liver and spleen and a sustained level of DFO in the blood. Three specific aims will be completed: In aim 1, we will optimize the Liposomal-DFO formulation. In aim 2, we will establish the Storage Stability of the Liposomal DFO Formulations. In aim 3 we will determine the liposomal DFO pharmacokinetics and biodistribution profile when administered by I.V. and subcutaneous routes. This targeted delivery of DFO to the main iron storage sites in the body will more effectively remove iron from deep tissue sites than infusion of non-encapsulated DFO, will infuse 1/8th of the currently used DFO dose in 1/40th of the current infusion time. The formulation will be easier and safer to administer than Desferal(R). If LDFO is validated, it would be a significant advance for the clinical treatment of transfusional iron overload in pediatric patients.