Novel therapeutic approach for severe ARDS with a potent pharmacologic allosteric hemoglobin modifier

急性呼吸窘迫综合征(ARDS)是一种危及生命的疾病，其特征是急性发作的非 心源性呼吸衰竭和低氧血症。因此，ARDS患者会出现严重的低氧血症。 导致严重的气体交换障碍，支持治疗的目标是防止关键组织 缺氧，可导致急性心脏骤停和死亡，或对 幸存者。在美国，ARDS每年影响近20万人，导致350万住院日和 近75,000人死亡。尽管我们对保护性通风策略和现代 先进的生命支持技术，如体外膜氧合(ECMO)，相关的死亡率 急性呼吸窘迫综合征的发病率仍然高得令人无法接受，而且20年来没有明显改善。事实上，中流砥柱 ICU的支持性治疗包括通过引入补充治疗来改善动脉血氧饱和度 氧气和机械通风支持呼吸，但这种措施的能力是有限的 以造福于患者。事实上，暴露在高比例氧气中实际上可能会增加危重病人的死亡风险。 病人。同样，机械通气的过度扩张会加重急性肺损伤，尽管 保护性肺通风的目的只是提供机械支持，而不会造成伤害。因此， 补充氧气和机械通风的最大限度治疗通常不足以维持生命，直到 肺恢复了。我们提出了一种新的治疗策略，使用一种小分子药物来改变治疗模式 加强支持性护理措施，有可能限制ARDS的发病率和死亡率。我们的治疗方案 候选的VZHE-039甘氨酸盐，一种天然芳香醛香兰素的水溶性合成类似物，是 一种高效的血红蛋白(Hb)变构修饰剂，证明了其快速有效地提高 静脉给药时Hb结合和转运O2的能力。芳香醛 VZHE-039的组分在α-裂隙中与N-末端的缬氨酸胺形成可逆希夫碱相互作用 Hb通过稳定其高O2亲和力状态来变构修饰Hb。其结果是快速的，药理学上的转变 Hb O2亲和力，可以增加安全边际，防止急性减饱和，并限制对更多 有创性机械通气或额外补充氧气。这种新颖的方法还有可能 推迟甚至阻止使用ECMO进行紧急救助的需要。我们的目标是提供确凿的证据 通过在猪严重ARDS的脂多糖内毒素模型中评估该方法的有效性来评估该方法的潜力。 在我们的第一阶段研究中显示出高度重复性和剂量依赖性的可喜结果之后 实现血红蛋白氧亲和力变化的药效学：一项高保真的明确疗效研究 大型动物模型将支持进入人类临床试验。

Acute respiratory distress syndrome (ARDS) is a life-threatening condition featuring acute onset of non- cardiogenic respiratory failure and hypoxemia. Consequently, patients with ARDS have severe hypoxemia due to a significant impairment of gas exchange, and the goal of supportive therapy is to prevent critical tissue hypoxia, which can cause acute cardiac arrest and death or have long-term neurologic consequences for survivors. ARDS affects almost 200,000 individuals annually in the US, leading to >3.5 million hospital days and nearly 75,000 deaths. Despite developments in our understanding of protective ventilation strategies and modern advanced life support techniques, such as extracorporeal membrane oxygenation (ECMO), mortality associated with ARDS remains unacceptably high and has not improved appreciably in two decades. Indeed, the mainstay of supportive therapy in the ICU includes improving arterial oxygen (O2) saturation by introducing supplemental O2 and supporting respiration with mechanical ventilation, but there are limits to the capacity of such measures to benefit patients. In fact, exposure to a high fraction of O2 may actually increase risk for mortality in critically ill patients. Similarly, excessive distention from mechanical ventilation can exacerbate acute lung injury, although the goal of protective lung ventilation is simply to offer mechanical support without inducing harm. Hence, maximal therapy with supplemental O2 and mechanical ventilation is often not sufficient to sustain life until the lungs recover. We propose a novel, paradigm shifting therapeutic strategy using a small molecule drug to enhance supportive care measures and potentially limit the morbidity and mortality of ARDS. Our therapeutic candidate, VZHE-039.glycine salt, a water-soluble synthetic analog of the natural aromatic aldehyde vanillin, is a highly potent allosteric modifier of hemoglobin (Hb) that demonstrated its ability to rapidly and potently increase the capacity of Hb to bind and transport O2 when administered intravenously to pigs. The aromatic aldehyde constituent of VZHE-039 forms reversible Schiff-base interactions with N-terminal valine amines in the α-cleft of Hb to allosterically modify Hb by stabilizing its high O2-affinity state. The result is a rapid, pharmacologic shift in Hb O2 affinity, which can increase the margin of safety to prevent acute desaturation and limit the need for more invasive mechanical ventilation or additional supplemental O2. This novel approach also has the potential to delay or even prevent the need for emergent salvage with ECMO. Our goal is to provide definitive evidence of the potential of this approach by assessing its efficacy in a LPS endotoxin model of severe ARDS in pigs. Following promising results in our Phase I study demonstrating highly reproducible and dose-dependent pharmacodynamics achieving shifts in hemoglobin oxygen affinity, a definitive efficacy study in a high fidelity large animal model would support advancement into a human clinical trial.