NanoDisk-Amphotericin B therapy for aspergillosis

NanoDisk-两性霉素 B 治疗曲霉菌病

• 批准号: 8012700
• 负责人: TRUDY M FORTE
• 金额: $ 72.62万
• 依托单位: LYPRO BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-05 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012700
• 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; Effectiveness; Growth; HIV; Health; Hepatic; Immunocompromised Host; In Vitro; Infection; Intravenous; Kidney; Life; 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

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（由申请人提供）：烟曲霉是一种机会致病性真菌，主要感染免疫功能低下的患者。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。由于极高的死亡率（约75%的人在感染后一年内死亡），艾滋病毒感染患者的烟曲霉感染是最相关的。由于患者往往太脆弱，无法进行侵入性或毒性治疗，治疗变得复杂。曲霉病的一线治疗是两性霉素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重要因素，并且是剂量限制的。因此，AMB对其治疗应用提出了一系列挑战。针对这一问题，Lypro- Biosciences, Inc.开发了NanoDisks (ND)，这是一种新型的脂质和蛋白质制剂，用于疏水药物的增溶和输送。NDs是直径8 - 15nm的圆盘状结构，由脂质双分子层组成，由稳定的载脂蛋白或肽模拟物包围。当AMB掺入NDs （ND-AMB）时，AMB的溶解度显著增加，毒性显著降低。此外，ND-AMB的安全剂量至少是AMB脱氧胆酸盐（真菌素——该药物的传统形式）的10倍。与AMB （AmBisome）的主要商业脂体制剂相比，ND-AMB对烟曲霉的最低抑制浓度在体外低25倍，在全身弥散性念珠菌病的动物模型中，ND-AMB的有效剂量低6倍。此外，与AmBisome（曲霉病临床治疗的一个关键参数）相比，ND-AMB具有快速起效的治疗效果，因为患者通常不会在感染的早期阶段被诊断出来。ND-AMB的效力增强，毒性降低，治疗起效快，使其成为治疗曲霉病的理想疗法。在拟议的项目中，我们将验证ND-AMB是一种治疗和预防小鼠播散性曲霉病的快速、有效和安全的疗法。由于肺曲霉病患者接受吸入治疗的能力较弱，因此将检查静脉注射ND-AMB对已确定的曲霉感染的疗效。将确定抗真菌效力、安全性和分布参数，从而产生用于评估ND-AMB有效性的临床相关数据集。由于曲霉感染的正常途径是通过吸入分生孢子，因此针对肺部的预防措施可能是最有效的。我们将验证吸入ND-AMB可以作为一种有效的预防曲霉病的假设。通过这一提议，我们将把以前的SBIR研究扩展到临床相关的场景，测试ND-AMB治疗和预防曲霉病的能力，曲霉病是对艾滋病毒感染者健康和生命的重大威胁。