Diabetic retinopathy (DR) is a neurovascular complication of diabetes mellitus and the leading cause of blindness in working age adults and elderly, affecting approximately 4.2 million diabetes patients in the US, of which 655,000 have vision-threatening DR. There is an urgent need for the development of additional approaches to prevent and treat diabetic retinopathy, as the current therapeutic interventions have limited efficacy and substantial drawbacks. In multiple preclinical studies, we and others have demonstrated the cytoprotective properties of low dose carbon monoxide (CO) in various disease states, including in ischemia- associated diseases such as DR To date, inhaled CO gas (iCO) and CO bound to carrier molecules (CORMs) have been the modalities of choice in the majority of animal and in all the clinical studies carried out to study the potential benefit of low dose CO. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable therapeutic options due to, with iCO, the risk of inadvertent exposure from the presence of compressed CO cylinders as well as difficulties in controlling dosing and, with CORMs, carrier molecule toxicology, stability, and CO release characteristics that have proven to be a substantial barrier to development. The objective of the proposed project is to investigate HBI-002, a novel oral CO drug product, to prevent and treat DR. The safety and tolerability of CO has been demonstrated in 25 successful Phase 1 and 2 clinical studies by others in other indications supported by well-defined preclinical data sets that led to approval by the FDA for human testing. HBI-002 comprises an oral formulation containing precise amounts of CO that are not bound to a carrier molecule (i.e. not a CORM). Preclinical in vivo pharmacokinetic studies demonstrated proof-of- concept feasibility, tolerability, and bioavailability. The next step in development is to demonstrate that HBI-002 is effective in clinically relevant animal models of DR and to better understand the potential mechanism(s) of action. Based upon the substantial literature of CO in protecting against ischemia-associated and ophthalmologic disease, our central hypothesis that will be tested in this project is: HBI-002 will prevent DR by reducing oxidative stress and inflammation. Public Health Relevance Statement PROJECT NARRATIVE This proposal is intended to support research evaluating whether HBI-002, an oral carbon monoxide (CO) therapeutic, can improve outcomes in animal models of diabetic retinopathy (DR). If successful, the project will provide proof-of-concept for further development of HBI-002 in DR as a promising therapeutic to improve outcomes in this devastating condition.
Project Terms: Adult ; 21+ years old ; Adult Human ; adulthood ; Affect ; Age ; ages ; Elderly ; advanced age ; elders ; geriatric ; late life ; later life ; older adult ; older person ; senior citizen ; Animals ; Antioxidants ; anti-oxidant ; Bilirubin ; Bilirubin IX alpha ; Biliverdine ; Biliverdin ; Dehydrobilirubin ; Ooecyan ; Uteroverdine ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Blood Vessels ; vascular ; Carbon Monoxide ; Clinical Research ; Clinical Study ; Clinical Trials ; Diabetes Mellitus ; diabetes ; Diabetic Retinopathy ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exhibits ; Eye ; Eyeball ; Fibrosis ; Gases ; Gastrointestinal tract structure ; Alimentary Canal ; Digestive Tract ; GI Tract ; Gastrointestinal Tract ; alimentary tract ; digestive canal ; Gene Expression ; Genes ; Health ; Heme ; Ferroprotoporphyrin ; Protoheme ; ferroheme ; heme oxygenase-1 ; HO-1 enzyme ; HO1 ; HO2 ; HSP32 ; hemeoxygenase 1 ; Human ; Modern Man ; Hyperglycemia ; hyperglycemic ; Inflammation ; Ischemia ; Light Coagulation ; Photocoagulation ; photocoagulation therapy ; Literature ; Methods ; Mus ; Mice ; Mice Mammals ; Murine ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Ophthalmology ; Pathology ; Patients ; Drug Kinetics ; Pharmacokinetics ; Phenotype ; Reperfusion Therapy ; reperfusion ; Reperfusion Injury ; Ischemia-Reperfusion Injury ; Reperfusion Damage ; Research ; Research Personnel ; Investigators ; Researchers ; Research Support ; Retina ; Retinal Degeneration ; degenerative retina diseases ; retina degeneration ; retinal degenerative ; retinal degenerative diseases ; Retinal Diseases ; Retinal Disorder ; retina disease ; retina disorder ; retinopathy ; Risk ; Safety ; Streptozocin ; STZ ; Streptozotocin ; Zanosar ; Technology ; Testing ; Time ; Toxicology ; Vision ; Sight ; visual function ; Visual impairment ; Diminished Vision ; Low Vision ; Partial Sight ; Reduced Vision ; Subnormal Vision ; vision impairment ; visually impaired ; Work ; Data Set ; Dataset ; retinal ischemia ; retina ischemia ; Apoptosis ; Apoptosis Pathway ; Programmed Cell Death ; Reactive Oxygen Species ; Active Oxygen ; Oxygen Radicals ; Pro-Oxidants ; Injury ; injuries ; base ; Left ; Acute ; Clinical ; Phase ; Histologic ; Histologically ; Biochemical ; Evaluation ; diabetic ; Oxidative Stress ; Therapeutic ; Fe element ; Iron ; Morphology ; Inflammatory ; Diabetes Complications ; Diabetes-Related Complications ; Diabetic Complications ; Complications of Diabetes Mellitus ; Contralateral ; Oral ; vision loss ; visual loss ; Blindness ; success ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; Structure ; novel ; Basic Research ; Basic Science ; Modality ; Anti-VEGF ; Anti-VEGF Humanized Monoclonal Antibody ; Anti-VEGF RhuMAb ; MoAb VEGF ; Monoclonal Antibody Anti-VEGF ; Recombinant Humanized Anti-VEGF Monoclonal Antibody ; Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor ; RhuMAb VEGF ; rhuMabVEGF ; bevacizumab ; intervention therapy ; Therapeutic Intervention ; Modeling ; Property ; drug development ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; preventing ; prevent ; Address ; Dose ; Data ; Preclinical Models ; Pre-Clinical Model ; in vivo ; Monitor ; Characteristics ; Development ; developmental ; pre-clinical ; preclinical ; preclinical study ; pre-clinical study ; Neuronal Injury ; neuron injury ; glycemic control ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; Diabetic mouse ; diabetes mouse model ; direct application ; protective effect ; Coupled ; innovation ; innovate ; innovative ; clinically relevant ; clinical relevance ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; Regimen ; Formulation ; neurovascular ; neuro-vascular ; neurovascular injury ; neuro-vascular damage ; neuro-vascular injury ; neurovascular damage ; improved outcome ; efficacy study ; Inhalation ; Inhaling ; human model ; model of human ; phase 1 testing ; phase 1 evaluation ; phase I evaluation ; phase I testing ; infection risk ; pharmacokinetics and pharmacodynamics ; PK/PD ;
