NanoDisk-Amphotericin B therapy for aspergillosis

描述(申请人提供)：烟曲霉是一种机会致病真菌，主要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的最常见原因。由于异常高的死亡率(75%的人在感染第一年内死亡)，艾滋病毒感染患者中的烟雾菌感染是最相关的。患者往往太脆弱，无法进行侵入性或毒性治疗，这使得治疗变得复杂。治疗曲霉菌病的一线药物是两性霉素B(AMB)，但它对肾脏有高度毒性，而且不溶于水。它的肾毒性可能是导致死亡率的一个重要因素，并且具有剂量限制。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.开发了纳米盘(ND)，这是一种用于增溶和输送疏水药物的脂类和蛋白质的新型制剂。NDS是直径8-15 nm的圆盘状结构，由稳定的载脂蛋白或多肽模拟物包围的脂双层组成。当AMB与NDS(ND-AMB)复配时，AMB的溶解度显著增加，毒性降低。此外，ND-AMB的剂量可以安全地超过AMB脱氧胆酸盐(Fungizone-该药物的传统形式)至少10倍的水平。与AMB(AmBisome)的主要商业脂质体配方相比，ND-AMB在体外对烟曲霉菌的最小抑制浓度低25倍，在系统播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相比，ND-AMB具有更快的疗效，AmBisome是临床治疗曲霉病的关键参数，因为患者通常在感染的早期阶段不被诊断。ND-AMB的增强效力、降低毒性和快速起效相结合，使其成为治疗曲霉病的理想疗法。在拟议的项目中，我们将检验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的假设。由于肺曲霉菌病患者接受吸入性治疗的能力较差，静脉注射(Iv)的疗效。使用ND-AMB将检查确定的曲霉感染情况。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吸入分生孢子，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可以有效预防曲霉菌病的假设。通过这项建议，我们将把以前的SBIR研究扩展到临床相关的情况，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患者的健康和生命的重大威胁。 公共卫生相关性：HIV感染患者中的烟曲霉菌感染具有极高的死亡率(75%在感染的第一年内死亡)。患者往往太脆弱，不能进行侵入性或毒性治疗。治疗曲霉菌病的一线药物是两性霉素B(AMB)，但它对肾脏有高度毒性，而且不溶于水。它的肾毒性可能是导致死亡率的一个重要因素，并且具有剂量限制。我们相信，我们将AMB重新配制成含有AMB的纳米盘(ND)的努力已经将其从一种略微有效的治疗方法转变为一种有效的治疗方法。这项研究的结果对ND-AMB发展为改进的静脉注射至关重要。以及以AMB为基础的吸入疗法，用于治疗和预防曲霉菌病；这是艾滋病毒感染患者的一个严重健康问题，中位生存期为3个月。静脉和吸入ND-AMB将为致命疾病带来有效的治疗和预防。

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.