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，呼吸道病毒感染的广谱预防和治疗是非常需要的。人副流感病毒（HPIV）是呼吸道病毒性疾病的重要组成部分。目前还没有批准的预防或治疗HPIV的治疗方法。该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。该项目的长期目标是将DAS181用于HPIV适应症的临床试验。DAS181是一种重组融合蛋白，由唾液酸酶催化结构域与上皮锚定序列融合而成，其功能是消除气道上皮上的唾液酸。DAS181目前处于临床开发阶段，用于治疗流感病毒（IFV）感染。ifv和hpiv有一个共同的途径，即病毒与细胞表面的唾液酸结合，作为感染的第一步。由于DAS181通过使唾液酸失活而起作用，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。本研究有两个具体目的：一是验证DAS181对HPIV临床分离株的体外疗效和药效学，二是通过DAS181预防和治疗的棉花大鼠模型验证DAS181对HPIV的体内疗效。为了在体外建立原理证明，将获得2或3个经证实为HPIV1的临床分离株。将建立至少20种不同的临床分离株，用于测试对DAS181的敏感性。DAS181在LLC-MK细胞中抑制HPIV感染的能力将被评估。不同HPIV分离株对DAS181的易感性将通过在相同病毒攻击水平下的EC50和EC90值进行比较。DAS181对临床HPIV分离株的潜在抗HPIV作用也将通过分化良好的人气道上皮培养（HAE）进行评估。该模型将允许评估DAS181暴露于HPIV感染的时间。将采用棉花大鼠HPIV模型来确定体内疗效。在建立模型以确定HPIV分离株的最佳感染后，DAS181将在预防HPIV前接种模型中进行效果评估。随后的棉花大鼠体内研究将确定DAS181治疗现有HPIV感染的时间过程。确定DAS181在HPIV感染中的药理学疗效这两个目标的实现，将为参与ins前期开发、IND提交以及最终开展该适应症的临床试验提供依据。由于DAS181已经处于流感适应症的I期临床试验中，因此在证明对HPIV具有有效活性后，向HPIV适应症的发展道路可能会相当快。