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）：曲曲霉是一种机会性的致病真菌，主要会感染免疫功能低下的患者。它是艾滋病毒患者，器官移植受者和癌症患者感染性肺炎死亡率的最常见原因。由于死亡率异常高（在感染的第一年，> 75％死亡），感染HIV感染患者的Fumigatus感染是最相关的。治疗使患者通常太脆弱或有毒疗法变得复杂。曲霉病的一线治疗方法是两性霉素B（AMB），但既高肾毒性又不溶于溶解。它的肾毒性可能是导致死亡率的重要因素，并且是剂量限制。因此，AMB对其治疗应用提出了一系列挑战。为了应对这个问题，Lypro-Biosciences，Inc。开发了纳米风险。 （ND-AMP）AMB溶解性和毒性的降低幅度急剧增加。在体外低25倍，在全身传播的念珠菌病的动物模型中，ND-AMB在低剂量下有效，ND-AMB具有迅速的治疗作用，与Ambisome相比，与患者的临床治疗中的关键参数相比。增强的效力，毒性降低和治疗快速发作的结合使ND-AMB成为治疗曲霉病的理想治疗方法。在拟议的项目中，我们将检验以下假设：ND-AMB是一种快速，有效且安全的治疗，用于治疗和预防小鼠的曲霉病。由于肺曲霉病的患者能够接受吸入疗法的能力，因此将检查静脉内（i.v.）施用的ND-AMB的功效，以针对已建立的曲霉感染进行检查。将确定抗真菌效力，安全性和分布的参数，从而产生临床相关的数据集，以评估ND-AMP有效性。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。我们将检验以下假设：吸入的ND-AMB可以作为预防曲霉病的有效预防性。通过该提案，我们将将以前的SBIR研究扩展到临床相关的情景中，测试ND-AMB对治疗和预防曲霉病的能力，这是对感染HIV感染患者的健康和生活的重大威胁。 公共卫生相关性：艾滋病毒感染患者的曲霉感染的死亡率异常高（在感染的第一年内> 75％死亡）。患者通常对于侵入性或有毒疗法太脆弱。曲霉病的一线治疗方法是两性霉素B（AMB），但既高肾毒性又不溶于溶解。它的肾毒性可能是导致死亡率的重要因素，并且是剂量限制。我们认为，我们将AMB重新制定为含有AMB的纳米风险（ND）的努力已将其从极有效的治疗转变为有效的治疗方法。这项研究的结果对于将ND-AMB开发到改进的i.v.中至关重要。以及基于AMB的吸入治疗和预防曲霉病的疗法；艾滋病毒感染患者的严重健康问题，中位生存期为3个月。静脉注射和可吸入的ND-AMB将带来有效的治愈方法，并预防致命疾病。