Targeting MMP9 to Improve Outcomes in Serious Influenza Infections

描述（由申请人提供）：尽管有疫苗可供使用并在全球范围内进行监测，但流感感染仍然是一个巨大的公共卫生问题。甲型流感病毒（IAV）的高突变率使病毒能够逃避自然和疫苗介导的免疫。此外，目前的抗病毒治疗不能防止IAV相关的死亡时，有一个在开始治疗延迟。因此，治疗流感疾病的新的治疗选择是当前的公共卫生优先事项。我们的初步研究确定MMP-9作为一个有吸引力的IAV治疗靶点。MMP- 9在感染季节性和H1N1 IAV的人类受试者的血浆样品中以及感染H1N1 IAV的小鼠的肺中显著上调。在小鼠中，Mmp-9增加了IAV相关的死亡率和晚期肺部炎症以及晚期肺部病毒负荷。我们提出在三个综合和高度协作的目标中测试“重新目的化的”治疗候选物（ADZ 1236）的治疗功效，所述治疗候选物选择性地且有效地抑制两个物种中IAV感染中的MMP-9活性。目的1将测试AZD 1236治疗感染BL 2 H1N1 IAV的小鼠的疗效。AZD 1236将在小鼠中单独进行试验，并与临床使用的抗病毒剂（神经氨酸酶抑制剂，奥司他韦）联合进行试验。将优化延迟开始治疗的方法，以模拟严重IAV感染的“真实世界”治疗方案。目的2将确定Mmp-9促进（和AZD 1236限制）小鼠严重IAV感染的机制。我们将研究H1N1感染的WT与Mmp-9-/-小鼠和Mmp-9骨髓嵌合小鼠，并使用体外方法来测试我们的假设，即Mmp-9通过切割宿主或病毒蛋白促进IAV疾病的不良后果。将鉴定这些Mmp-9底物。目标3将测试AZD 1236在感染BL 2 H1N1和BL 3高致病性禽流感（HPAI）H5 N1毒株的雪貂中的治疗效果（以及在H7N9 IAV感染的雪貂中，如果该毒株在资助期间作为流行或大流行毒株出现）。我们的研究将确定AZD 1236介导的MMP-9抑制是否在小型和大型动物中对IAV具有足够的治疗功效，从而满足FDA“两种动物规则”，以证明申请FDA批准的功效。本文提出的工作的成功完成可能为严重流感介导的肺部疾病提供“一流”的治疗干预。

DESCRIPTION (provided by applicant): Influenza infection remains an enormous public health concern despite the availability of vaccines and worldwide surveillance. The high mutation rates of influenza A viruses (IAVs) enable the viruses to evade natural and vaccine-mediated immunity. Also, current anti-viral therapies do not prevent IAV-related deaths when there is a delay in initiating treatment. Thus, new therapeutic options for treating influenza disease are an immediate public health priority. Our pilot studies identify MMP-9 as an attractive IAV therapeutic target. MMP- 9 is strikingly upregulated in plasma samples from human subjects infected with seasonal and H1N1 IAV and in lungs from mice infected with H1N1 IAV. In mice, Mmp-9 increases IAV-associated mortality and late-stage lung inflammation and late-stage lung viral burdens. We proposed to test the therapeutic efficacy of a "re- purposed" therapeutic candidate (ADZ1236) that selectively and potently inhibits MMP-9 activity in IAV infections in two species in three integrated and highly collaborative aims. Aim 1 will test the therapeutic efficacy of AZD1236 therapy in mice infected with BL2 H1N1 IAV. AZD1236 will be tested in mice alone and in combination with a clinically-used antiviral agent (the neuraminidase inhibitor, oseltamivir). A delayed initiation of treatment approach will be optimized to model "rea-world" treatment scenarios for serious IAV infections. Aim 2 will identify the mechanisms by which Mmp-9 promotes (and AZD1236 limits) serious IAV infections in mice. We will study H1N1-infected WT vs. Mmp-9-/- mice and Mmp-9 bone marrow chimeric mice and use in vitro approaches to test our hypothesis that Mmp-9 promotes adverse outcomes in IAV disease by cleaving host or viral proteins. These Mmp-9 substrates will be identified. Aim 3 will test the therapeutic efficacy of AZD1236 in ferrets infected with BL2 H1N1 and the BL3 highly pathogenic avian influenza (HPAI) H5N1 strain (and in H7N9 IAV-infected ferrets if this strain emerges as an epidemic or pandemic strain during the funding period). Our studies will determine whether AZD1236-mediated MMP-9 inhibition has therapeutic efficacy against IAV in both small and large animals sufficient to thereby satisfy the FDA "Two Animal Rule" required to demonstrate efficacy to apply for FDA approval. Successful completion of the work proposed herein may provide a "first in class" therapeutic intervention for serious influenza-mediated lung disease.