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NanoDisk-Amphotericin B therapy for aspergillosis

NanoDisk-两性霉素 B 治疗曲霉菌病

基本信息

批准号：
8082636
负责人：
TRUDY M FORTE
金额：
$ 74.57万
依托单位：
LYPRO BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-05 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8082636
关键词：
Adverse effects AmBisome Amphotericin B Animal Model Antibiotics Antifungal Agents Apolipoproteins Aspergillosis Aspergillus Aspergillus fumigatus Attenuated Biological Biological Availability Breathing Caliber Cancer Patient Candida Candidiasis Clinical Clinical Treatment Complex Data Data Set Development Diagnosis Disease Disseminated candidiasis Dose Dose-Limiting Drug Formulations Drug Kinetics Early Diagnosis Early treatment Effectiveness Growth HIV Health Hepatic Immunocompromised Host In Vitro Infection Intravenous Kidney Lipid Bilayers Lipids Liposomes Lung Marketing Measures Modeling Mus Mycoses Nephrotoxic Organ Transplantation Patients Peptides Pharmaceutical Preparations Phase Plasma Polyenes Powder dose form Preparation Prevention Process Property Proteins Relative (related person)Route Safety Shapes Small Business Innovation Research Grant Solubility Staging Structure Testing Therapeutic Therapeutic Effect Time Toxic effect Toxicity Attenuation Translating Transplant Recipients Treatment Efficacy Ursidae Family amphotericin B-deoxycholate aqueous base clinically relevant deoxycholate effective therapy fungus improved in vivo mimetics mortality nanodisk nephrotoxicity novel particle prevent prophylactic public health relevance remediation response self assembly

项目摘要

DESCRIPTION (provided by applicant): Aspergillus fumigatus is an opportunistic pathogenic fungus that predominantly infects immunocompromised patients. It is the most common cause of infectious pneumonic mortality in HIV patients, organ transplant recipients, and cancer patients. A. fumigatus infection in HIV-infected patients is most pertinent due to the exceptionally high mortality rate (>75% die within the first year of infection). Treatment is complicated by the fact that patients are often too fragile for invasive or toxic therapies. A first-line treatment for aspergillosis is amphotericin B (AMB) but it is both highly nephrotoxic and insoluble. Its nephrotoxicity can be a significant contributing factor to mortality and is dose limiting. Thus, AMB presents an array of challenges to its therapeutic application. In response to this problem, Lypro- Biosciences, Inc. has developed NanoDisks" (ND), a novel preparation of lipid and protein for the solubilization and delivery of hydrophobic drugs. NDs are 8 - 15 nm diameter disc-shaped structures composed of a lipid bilayer circumscribed by a stabilizing apolipoprotein or peptide mimetic. When AMB is incorporated into NDs (ND-AMB), there is a dramatic increase in AMB solubility and reduction in its toxicity. Furthermore, ND-AMB can be safely dosed to levels at least 10-fold greater than that of AMB deoxycholate (Fungizone - the conventional form of the drug). In comparison to a leading commercial liposomal formulation of AMB (AmBisome), the minimal inhibitory concentration of ND-AMB against A. fumigatus is 25-fold lower in vitro and in an animal model of systemically disseminated candidiasis, ND- AMB is effective at a 6-fold lower dose. Moreover, ND-AMB has a rapid onset of therapeutic effect in comparison to AmBisome, a critical parameter in the clinical treatment of aspergillosis, as patients are normally not diagnosed at an early stage of infection. The combination of enhanced potency, reduced toxicity, and rapid onset of therapy make ND-AMB an ideal therapeutic for the treatment of aspergillosis. In the proposed project we will test the hypothesis that ND-AMB is a fast acting, potent and safe therapy for treating and preventing disseminated aspergillosis in mice. Because patients with pulmonary aspergillosis are less capable of taking in inhaled therapies, the efficacy of intravenously (i.v.) administered ND-AMB will be examined against established Aspergillus infection. Parameters of antifungal potency, safety, and distribution will be determined, yielding a clinically relevant dataset for assessment of ND-AMB effectiveness. Because the normal route of Aspergillus infection is through inhalation of conidia, prophylactic measures directed to the lung may be most effective. We will test the hypothesis that inhaled ND-AMB can serve as an effective prophylactic for the prevention of aspergillosis. Through this proposal we will extend previous SBIR studies into clinically relevant scenarios, testing the ability of ND-AMB to remediate and prevent aspergillosis, a significant threat to the health and lives of HIV-infected patients. PUBLIC HEALTH RELEVANCE: Aspergillus fumigatus infection in HIV-infected patients has an exceptionally high mortality rate (>75% die within the first year of infection). Patients are often too fragile for invasive or toxic therapies. A first-line treatment for aspergillosis is amphotericin B (AMB) but it is both highly nephrotoxic and insoluble. Its nephrotoxicity can be a significant contributing factor to mortality and is dose limiting. We believe our efforts to reformulate AMB into AMB-containing NanoDisks (ND) have transformed it from a marginally effective treatment to a potent cure. Results from this study are essential for the development of ND- AMB into an improved i.v. and inhaled AMB-based therapy for the treatment and prevention of aspergillosis; a serious health issue for HIV infected patients, wherein median survival is 3 months. Intravenous and inhalable ND-AMB will bring to bear an effective cure and preventative to a deadly disease.

描述（由申请方提供）：烟曲霉是一种机会致病真菌，主要感染免疫功能低下患者。它是HIV患者、器官移植受者和癌症患者感染性肺炎死亡的最常见原因。a. HIV感染患者的烟曲霉感染是最相关的，因为其死亡率非常高（> 75%在感染的第一年内死亡）。由于患者往往过于脆弱，无法接受侵入性或毒性治疗，因此治疗变得复杂。曲霉菌病的一线治疗是曲霉素B（AMB），但它具有高度肾毒性且不溶性。它的肾毒性可能是死亡率的一个重要因素，并且是剂量限制性的。因此，AMB对其治疗应用提出了一系列挑战。为了解决这个问题，Lypro-Biosciences，Inc.已经开发了纳米脂质体（ND），一种用于溶解和递送疏水性药物的脂质和蛋白质的新制剂。ND是8 - 15 nm直径的盘状结构，由稳定载脂蛋白或肽模拟物包围的脂质双层组成。当AMB掺入ND（ND-AMB）中时，AMB溶解度急剧增加，其毒性降低。此外，ND-AMB可以安全地给药到比AMB脱氧胆酸盐（Fungizone-药物的常规形式）高至少10倍的水平。与AMB的主要商业脂质体制剂（AmBisome）相比，ND-AMB对A.在体外和全身播散性念珠菌病的动物模型中，ND-AMB在低6倍的剂量下有效。此外，与AmBisome相比，ND-AMB具有快速起效的治疗效果，AmBisome是曲霉病临床治疗中的关键参数，因为患者通常不会在感染的早期阶段被诊断出来。增强的效力、降低的毒性和快速起效的治疗组合使ND-AMB成为治疗曲霉病的理想治疗剂。在拟议的项目中，我们将测试的假设，ND-AMB是一种快速，有效和安全的治疗和预防小鼠播散性曲霉病的疗法。由于肺曲霉病患者接受吸入治疗的能力较低，因此静脉内（i.v.）将检查施用的ND-AMB对确定的曲霉菌感染的影响。将确定抗真菌效力、安全性和分布的参数，产生用于评估ND-AMB有效性的临床相关数据集。由于曲霉菌感染的正常途径是通过分生孢子的吸入，针对肺部的预防措施可能是最有效的。我们将检验吸入性ND-AMB可以作为预防曲霉病的有效预防剂的假设。通过这项提案，我们将把以前的SBIR研究扩展到临床相关场景，测试ND-AMB修复和预防曲霉病的能力，曲霉病是对艾滋病毒感染患者健康和生命的重大威胁。公共卫生关系：HIV感染患者中的烟曲霉感染具有极高的死亡率（> 75%在感染的第一年内死亡）。患者通常过于脆弱，无法接受侵入性或毒性治疗。曲霉菌病的一线治疗是曲霉素B（AMB），但它具有高度肾毒性且不溶性。其肾毒性可能是死亡率的一个重要因素，并且具有剂量限制性。我们相信，我们将AMB重新配制成含AMB的纳米颗粒（ND）的努力已经将其从一种边缘有效的治疗方法转变为一种有效的治疗方法。该研究的结果对于将ND-AMB开发成用于治疗和预防曲霉病的改进的基于静脉内和吸入AMB的疗法是必不可少的;曲霉病是HIV感染患者的严重健康问题，其中中位生存期为3个月。静脉注射和吸入ND-AMB将带来承担一个有效的治疗和预防致命的疾病。