Document text
Principal Investigator: John A Rathmacher
Organization: MTI BIOTECH, INC.
Fiscal Year: 2024
Award: $957,913
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Although the ubiquity of metabolic problems in pulmonary hypertension (PH) has been known for more than a
decade, a wealth of new details on the nature of this problem presents the opportunity for intervention. A
combination of experimental work in cells and animals and early trials in humans, suggests that these
metabolic problems are part of the causation for PH, and that inactivation of the mitochondrial lysine
deacetylase SIRT3 is a central node in regulating the metabolic defects. A vicious cycle exists in which a
triggering event or mutation increases reactive oxygen species (ROS), which produces reactive lipids, which
adduct and inactivate SIRT3, causing metabolic changes that result in further increased ROS. Here, we break
this cycle using 2-HOBA, a small molecule which can effectively soak up reactive lipids in vivo and our
preliminary studies show that 2-HOBA is a safe compound and in IND enabling animal toxicity and human
safety trials and shows great promise in treating the core molecular defects in PH. Our preliminary data and
Phase I studies demonstrate not only clear positive impact on reducing pulmonary vascular resistances in
Group I and II PH, and both cytokine and molecular biomarkers of disease, but also indicated the potential for
a substantial positive effect on heart function under load stress. In this Phase II project, we will establish the
remaining data needed to proceed to commercialization through the following aims: 1) we will test the safety
and molecular efficiency of 2-HOBA in PH patients in a small open label mechanistic pilot trial with of two
weeks of 2-HOBA exposure; 2) we will demonstrate efficacy of 2HOBA in improving function of the right
ventricle under stress in a well-established sheep model; and 3) we will test effectiveness of 2-HOBA alone
and in the context of standard-of-care in mouse models and large animals. 2-HOBA is an entirely new
approach to solving a molecular problem that several existing clinical trials and case reports have tried to
resolve, but so far with limited success. The specific mechanism of action of 2-HOBA should allow it to
succeed where other interventions have failed.
Terms: <ACT2><AT744.1><Acetylation><Act-2><Active Oxygen><Affinity><After Care><After-Treatment><Aftercare><Agreement><Animal Model><Animal Models and Related Studies><Animals><BMPR-II><BMPR2><BMPR2 gene><BRK-3 protein><Binding><Biological Markers><Blood><Blood Reticuloendothelial System><Bone Morphogenetic Protein Receptor, Type II (Serine/Threonine Kinase) Gene><CCL4><CCL4 gene><Cardiac><Cardiac Output><Case Study><Causality><Cell Body><Cells><Ceramides><Cessation of life><Chemokine (C-C Motif) Ligand 4><Chemokine, CC Motif, Ligand 4><Clinical Trials><Combined Modality Therapy><Data><Deacetylase><Death><Defect><Disease><Disease Progression><Disorder><EFRAC><Echocardiogram><Echocardiography><Effectiveness><Ejection Fraction><Endothelin Receptor Antagonist><Etiology><Event><Fats><Fatty Acids><Fatty acid glycerol esters><Feedback><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Gln><Glutamine><Heart><High Fat Diet><Human><Hypoxia><Hypoxic><Immune Activation 2><Insulin Resistance><International><Intervention><Intervention Strategies><L-Glutamine><L-Lysine><Length of Life><Life><Lipids><Literature><Longevity><Lung><Lung Respiratory System><Lysine><MIP1B><MIP1B1><Macrophage Inflammatory Protein 1-Beta><Metabolic><Metabolic Marker><Metabolic syndrome><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Molecular><Molecular Interaction><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutant Strains Mice><Mutation><Nature><Oxygen Deficiency><Oxygen Radicals><Participant><Patients><Phase><Phase I Study><Physiologic><Physiological><Pro-Oxidants><Prostacyclins><Prostaglandins I><Protein Acetylation><Proteins><Publishing><Pulmonary Hypertension><Pulmonary Vascular Resistance><Q Levoglutamide><Q. Levoglutamide><Reactive Oxygen Species><Research><Right Ventricles><Right ventricular structure><Risk><SCYA4><Safety><Small Inducible Cytokine A4><Stress><Testing><Toxic effect><Toxicities><Transthoracic Echocardiography><Treprostinil><Vasodilating Agent><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Walking><Work><adduct><ambrisentan><analog><bio-markers><biologic marker><biomarker><blood vessel occlusion><bone morphogenetic protein receptor II><bone morphogenetic protein receptor type II><cardiac function><case report><causation><combination therapy><combined modality treatment><combined treatment><commercialization><cytokine><disease causation><drug efficacy><effectiveness testing><fatty acid oxidation><function of the heart><functional improvement><genome mutation><glucose metabolism><heart function><heart output><heart sonography><human disease><improve function><improved><improved functional outcomes><in vivo><inhibitor><insulin resistant><insulin tolerance><interventional strategy><loss of function><lung pressure><mitochondrial><model of animal><molecular biomarker><molecular marker><mouse model><mouse mutant><multi-modal therapy><multi-modal treatment><murine model><mutant><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><open label><open label study><ovine animal model><ovine model><phase 1 study><pilot trial><post treatment><primary end point><primary endpoint><pulmonary><pulmonary pressure><response><right heart failure><right sided heart failure><right ventricle failure><right ventricle remodeling><right ventricular failure><right ventricular heart failure><right ventricular remodeling><safety testing><sheep model><small molecule><standard of care><success><tadalafil><treatment effect><trial design><type II BMP receptor><uptake>