Proof-of-Principle Studies of DAS181 for Parainfluenza Virus Infection

DAS181 治疗副流感病毒感染的原理验证研究

• 批准号: 7804815
• 负责人: Fang Fang
• 金额: $ 30万
• 依托单位: NEXBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2011-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7804815
• 关键词: Address; Applications Grants; Binding; Catalytic Domain; Cell surface; Cells; Child; Clinical; Clinical Trials; Conduct Clinical Trials; Cotton Rats; Development; Epithelium; Goals; Human; Human Parainfluenza Virus 1; In Vitro; Infection; Infection prevention; Influenza; Laboratory Animals; Medical; Modeling; Morbidity - disease rate; Neuraminidase; Parainfluenza; Parainfluenza Virus Infections; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Predisposition; Prevention; Program Development; Prophylactic treatment; Recombinant Fusion Proteins; Safety; Sialic Acids; Small Business Innovation Research Grant; Testing; Therapeutic; Time; Treatment Protocols; Vaccines; Viral; Virus; Virus Diseases; Work; airway epithelium; burden of illness; in vivo; influenzavirus; mortality; novel; parainfluenza virus; prophylactic; public health relevance; receptor; respiratory; respiratory virus; socioeconomics; therapy development

DESCRIPTION (provided by applicant): Broad-spectrum prophylaxis and therapeutics for respiratory viral infections are highly desirable due to the immense socioeconomic burden imposed by the respiratory viruses. Human parainfluenza viruses (HPIV) represent a significant portion of respiratory viral disease. There are currently no approved treatments for the prevention or treatment of HPIV. The aims of this proposal are the first steps in a clinical development program to address this unmet medical need. The long-term objective of this project is to bring DAS181 into clinical trials in an HPIV indication. DAS181 is a recombinant fusion protein composed of a sialidase catalytic domain fused with an epithelium-anchoring sequence which functions by eliminating sialic acids on the airway epithelium. DAS181 is currently in clinical development for treatment of influenza virus (IFV) infection. IFVs and HPIVs share a common pathway of virus binding to sialic acids on the surface of cells as the initial step in infection. Since DAS181 works by inactivating sialic acid, the drug potentially confers very broad protection against any virus utilizing binding to sialic acid to gain entry into the cell. There are two specific aims of this proposal: first, to demonstrate the in vitro efficacy and pharmacodynamics of DAS181 against clinical isolates of HPIV and second, to demonstrate the in vivo efficacy of DAS181 against HPIV using a cotton rat model with DAS181 prophlyaxis and treatment. To establish the proof-of-principle in vitro, clinical isolates confirmed to be HPIV1, 2 or 3 will be obtained. At least 20 different clinical isolates will be established for testing sensitivity to DAS181. The ability of DAS181 to inhibit HPIV infection in LLC-MK cells will be evaluated. The susceptibility of various HPIV isolates to DAS181 will be compared by EC50 and EC90 values at an equal level of viral challenge. The potential anti- HPIV effect of DAS181 against clinical HPIV isolates will also be evaluated using the well-differentiated human airway epithelium culture (HAE). This model will allow the assessment of time of DAS181 exposure on the infection of HPIV. The cotton rat model of HPIV will be used to determine in vivo efficacy. Following the establishment of the model to determine the optimum infection of HPIV isolates, the efficacy of DAS181 will be evaluated in the prophylaxis, pre-HPIV inoculation model. Subsequent in vivo studies in cotton rats will define the time course of DAS181 treatment for existing HPIV infection. Accomplishing these two aims of defining pharmacological efficacy of DAS181 in HPIV infection will provide the rationale for engaging in pre-INS development, IND submission, and eventually the conduct of clinical trials in this indication. As DAS181 is already in a Phase I clinical trial for an influenza indication, the development path forward into an HPIV indication could be quite rapid upon this demonstration of potent activity against HPIV. PUBLIC HEALTH RELEVANCE: There is currently no treatment for human parainfluenza viral (HPIV) infection and no vaccine for prevention of infection. Yet HPIV represents a significant disease burden, especially for children, and represents a large unmet medical need. The proposed studies will establish Fludase(R), a novel recombinant fusion protein, as a potential drug for HPIV infections.

描述（由申请人提供）：由于呼吸道病毒造成的巨大社会经济负担，因此非常需要呼吸道病毒感染的广谱预防和治疗。人副流感病毒（HPIV）代表呼吸道病毒疾病的重要部分。目前还没有批准用于预防或治疗HPIV的治疗方法。本提案的目的是临床开发计划的第一步，以解决这一未满足的医疗需求。本项目的长期目标是将DAS 181纳入HPIV适应症的临床试验。DAS 181是一种重组融合蛋白，由与上皮锚定序列融合的唾液酸酶催化结构域组成，其功能是消除气道上皮上的唾液酸。DAS 181目前正在临床开发中，用于治疗流感病毒（IFV）感染。IFV和HPIV共享病毒结合细胞表面上的唾液酸作为感染的初始步骤的共同途径。由于DAS 181通过灭活唾液酸发挥作用，因此该药物可能对任何利用与唾液酸结合进入细胞的病毒提供非常广泛的保护。本提案有两个具体目的：第一，证明DAS 181对HPIV临床分离株的体外疗效和药效学，第二，使用DAS 181预裂解和处理的棉鼠模型证明DAS 181对HPIV的体内疗效。为了建立体外原理验证，将获得经证实为HPIV 1、2或3的临床分离株。将建立至少20种不同的临床分离株，用于检测对DAS 181的敏感性。将评价DAS 181抑制LLC-MK细胞中HPIV感染的能力。在相同病毒攻毒水平下，通过EC 50和EC 90值比较各种HPIV分离株对DAS 181的敏感性。还将使用分化良好的人气道上皮细胞培养物（HAE）评价DAS 181对临床HPIV分离株的潜在抗HPIV作用。该模型将允许评估DAS 181暴露时间对HPIV感染的影响。将使用HPIV的棉鼠模型来确定体内功效。在建立模型以确定HPIV分离株的最佳感染后，将在预防性、HPIV接种前模型中评价DAS 181的疗效。随后在棉鼠中进行的体内研究将确定DAS 181治疗现有HPIV感染的时间进程。实现确定DAS 181在HPIV感染中药理学疗效的这两个目标将为参与INS前开发、IND提交以及最终在该适应症中开展临床试验提供依据。由于DAS 181已处于流感适应症的I期临床试验中，因此在证明具有抗HPIV的强效活性后，开发HPIV适应症的路径可能相当迅速。 公共卫生相关性：目前没有人副流感病毒（HPIV）感染的治疗方法，也没有预防感染的疫苗。然而，HPIV是一个重大的疾病负担，特别是对儿童，并代表了一个巨大的未满足的医疗需求。拟议的研究将建立Fludase（R），一种新的重组融合蛋白，作为一种潜在的药物HPIV感染。