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 dueto a significant impairment of gas exchange, and the goal of supportive therapy is to prevent critical tissuehypoxia, which can cause acute cardiac arrest and death, or have long-term neurologic consequences forsurvivors. ARDS affects almost 200,000 individuals annually in the US, leading to >3.5 million hospital days andnearly 75,000 deaths. Despite developments in our understanding of protective ventilation strategies and modernadvanced life support techniques, such as extracorporeal membrane oxygenation (ECMO), mortality associatedwith ARDS remains unacceptably high and has not improved appreciably in two decades. Indeed, the mainstayof supportive therapy in the ICU includes improving arterial oxygen (O2) saturation by introducing supplementalO2 and supporting respiration with mechanical ventilation, but there are limits to the capacity of such measuresto benefit patients. In fact, exposure to a high fraction of O2 may actually increase risk for mortality in critically illpatients. Similarly, excessive distention from mechanical ventilation can exacerbate acute lung injury, althoughthe 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 thelungs recover. We propose a novel, paradigm shifting therapeutic strategy using a small molecule drug toenhance supportive care measures and potentially limit the morbidity and mortality of ARDS. Our therapeuticcandidate, TD-7, a synthetic analog of the natural aromatic aldehyde vanillin, is a highly potent, short actingallosteric modifier of hemoglobin (Hb) that increases the capacity of Hb to bind and transport O2 by stabilizing itsquaternary structure in a high O2-affinity state. This pharmacologic effect can improve the margin of safety byincreasing O2 saturation at critical PO2 levels and prevent acute desaturation events without requiring moreinvasive mechanical ventilation or additional supplemental O2. This intervention also has the potential to delayor even prevent the need for emergent ECMO. Importantly, preliminary evidence for this approach demonstratesthat improvements in arterial O2 saturation with high Hb O2 affinity do not compromise tissue O2 unloading and,instead, effectively reduce tissue hypoxia during an ARDS insult. While preliminary studies establish aromaticaldehyde-containing compounds, such as TD-7, as a promising clinical approach to ARDS, our ultimate goal isto provide definitive evidence of efficacy in a high fidelity porcine ARDS model to support advancement of thisdrug candidate to human clinical trials. This will be achieved in a step-wise approach: first, with the optimizationof intravenous formulation and delivery of TD-7 to achieve targeted in vivo pharmacodynamic effects ("dose-finding') in mini-pigs in Phase I, and subsequently, with the performance of a definitive efficacy study to assessoxygenation and prevention of tissue hypoxia in a porcine ARDS model in Phase II.
Public Health Relevance Statement: Acute Respiratory Distress Syndrome (ARDS) is a life-threatening condition that can result in acute respiratory
failure and severe hypoxemia due to a significant impairment of gas exchange. ARDS affects approximately
200,000 individuals annually in the US, and, despite medical advances in the understanding of protective
ventilation strategies and modern life support techniques, leads to nearly 75,000 deaths, with an unacceptably
high mortality rate that has not improved in two decades. We propose the development of a novel aromatic
aldehyde-containing drug candidate, TD-7, which can increase the capacity of hemoglobin to bind and transport
oxygen, and therefore improve the margin of safety for ARDS patients without requiring more invasive
mechanical ventilation or additional supplemental oxygen, and hopefully also delay or prevent the need for
advanced life support techniques, such as extracorporeal membrane oxygenation (ECMO).
Project Terms: Affect ; Aldehydes ; Amines ; amine ; Cations ; High Pressure Liquid Chromatography ; HPLC ; High Performance Liquid Chromatography ; High Speed Liquid Chromatography ; Clinical Trials ; Critical Illness ; Critically Ill ; Cessation of life ; Death ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Excipients ; Extracorporeal Membrane Oxygenation ; Gases ; Goals ; Heart Arrest ; Asystole ; Cardiac Arrest ; Hemoglobin ; Human ; Modern Man ; In Vitro ; Length of Stay ; Number of Days in Hospital ; hospital days ; hospital length of stay ; hospital stay ; Lung ; Lung Respiratory System ; pulmonary ; Methods ; Modernization ; Morbidity - disease rate ; Morbidity ; mortality ; Oxygen ; O element ; O2 element ; Patients ; Pharmacology ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Respiration ; respiratory mechanism ; Adult Respiratory Distress Syndrome ; ARDS ; Acute Respiratory Distress ; Acute Respiratory Distress Syndrome ; Adult ARDS ; Adult RDS ; Da Nang Lung ; Shock Lung ; Stiff lung ; wet lung ; Safety ; Schiff Bases ; Solubility ; Family suidae ; Pigs ; Suidae ; Swine ; porcine ; suid ; Miniature Swine ; Minipigs ; mini pig ; mini-swine ; miniswine ; Time ; Tissues ; Body Tissues ; Valine ; L-Valine ; vanillin ; 4-hydroxy-3-methoxybenzaldehyde ; vanillaldehyde ; Measures ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; Ï Proteins ; Dissociation ; Injectable ; base ; improved ; Mechanical ventilation ; mechanical respiratory assist ; mechanically ventilated ; Left ; Acute ; Clinical ; Refractory ; Phase ; Medical ; Neurologic ; Neurological ; Survivors ; Individual ; Hypoxia ; Hypoxic ; Oxygen Deficiency ; Acute Lung Injury ; Acute Pulmonary Injury ; analog ; Acute respiratory failure ; Therapeutic ; Exposure to ; Supportive Therapy ; Supportive care ; Intravenous ; Whole Blood ; Cardiac Death ; Life ; mechanical ; Mechanics ; Hour ; Event ; Techniques ; Particulate ; adduct ; oxygen transport ; Performance ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Structure ; novel ; Prevention ; hypoxemic ; Hypoxemia ; Pharmacodynamics ; Modeling ; Sampling ; Property ; Intervention Strategies ; interventional strategy ; Intervention ; lung failure ; pulmonary failure ; Respiratory Failure ; Molecular Interaction ; Binding ; preventing ; prevent ; small molecule ; Dose ; Affinity ; in vivo ; Preparation ; Development ; developmental ; cost ; scale up ; N-terminal ; NH2-terminal ; Impairment ; tertiary care ; novel therapeutic intervention ; new therapeutic approach ; new therapeutic intervention ; new therapeutic strategies ; new therapy approaches ; novel therapeutic approach ; novel therapeutic strategies ; novel therapy approach ; drug candidate ; Formulation ; efficacy study ; therapeutic candidate ; mortality risk ; death risk ; pharmacokinetics and pharmacodynamics ; PK/PD ; ventilation ; supplemental oxygen ; porcine model ; pig model ; piglet model ; swine model ;
