SBIR-STTR Award

The goal of the proposed project is to evaluate the potential of HBI-002, a novel oral formulation of carbon monoxide (CO), as a neuroprotective agent in Parkinson’s disease (PD). A growing body of research suggests that low doses of CO - and the heme oxygenase (HO) enzymes that generate endogenous CO - protect against neuronal cell loss in PD, and epidemiologic studies have associated cigarette smoking with a lower risk of PD. Together, these observations suggest that low doses of CO may be neuroprotective in PD. Nicotine does not appear to underlie the protective effect of tobacco, as a clinical study of nicotine in PD did not show significant improvement. At low levels (<10% CO-hemoglobin [COHb]), such as found in smokers, CO has been shown to have marked anti-apoptotic, anti-oxidant, and anti-inflammatory properties, and it has become a promising therapeutic under study for multiple neurologic and non-neurologic diseases. CO is generated by heme oxygenase 1 (HO-1) and 2 (HO-2), which transform the toxic species heme into CO, biliverdin, and iron. Converging evidence links the function of HO-1 and HO-2 to neuroprotection in PD, and the literature indicates that CO is protective in a PD model. The clinical safety and tolerability of CO at levels up to 13.9% COHb has been demonstrated in 25 Phase 1 and Phase 2 clinical trials (not in PD, but including in subarachnoid hemorrhage) using a variety of forms of CO administration, and there are ongoing clinical studies with CO. The absence of toxicity of CO at low COHb levels has been well demonstrated in the literature, providing supportive safety data for the COHb levels under consideration for PD. However, barriers to chronic dosing of CO with prior therapeutic administrative approaches have prevented the development of a CO therapeutic for chronic use, as would be the case in PD. HBI-002, a novel oral CO drug product, is being developed for the treatment of PD. The administration of a defined dose of CO delivered by oral administration of HBI-002 enables further development of CO as a therapeutic while obviating the problems associated with previously studied CO administration strategies, including, for inhaled CO, accidental inhalation exposure due to the need for compressed CO cylinders and imprecise dosing, and, for carrier molecule-bound CO (CORMs), toxicological concerns with carrier molecules. Pharmacokinetic and pharmacodynamic studies in mice, rats, pigs, and dogs with oral HBI-002 have demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development, as presented in this proposal, is to confirm the neuroprotective potential of HBI-002 in animal models of PD and to better understand the mechanisms of neuroprotection. For this purpose, we will assess the efficacy of HBI-002 in multiple in vivo PD models in two different species. In these models we will assess HBI-002 rescue of striatal dopamine loss, substantia nigra dopamine cell loss, and motor impairment; and we will explore the impact of HBI-002 on inflammatory cascades, Nrf-2 and HO-1 pathways, and mitochondrial biogenesis. Public Health Relevance Statement PROJECT NARRATIVE This application aims to evaluate whether HBI-002, an oral carbon monoxide (CO) therapeutic, can improve outcomes in rodent models of Parkinson’s disease (PD). If successful, this research will provide critical proof- of-concept for further development of HBI-002 in PD to prevent the progression of this devastating disease.

Project Terms:
Oral Administration ; Oral Drug Administration ; intraoral drug delivery ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Antioxidants ; anti-oxidant ; Award ; Biliverdine ; Biliverdin ; Dehydrobilirubin ; Ooecyan ; Uteroverdine ; Biogenesis ; Origin of Life ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Brain ; Brain Nervous System ; Encephalon ; Carbon Monoxide ; Cause of Death ; Cell Culture Techniques ; cell culture ; Cell Death ; necrocytosis ; Cell Survival ; Cell Viability ; Cells ; Cell Body ; Clinical Research ; Clinical Study ; Clinical Trials ; Corpus striatum structure ; Corpus Striatum ; Striate Body ; Striatum ; striatal ; Disease ; Disorder ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Dopamine ; Hydroxytyramine ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Enzymes ; Enzyme Gene ; Gases ; Genes ; Goals ; Heme ; Ferroprotoporphyrin ; Protoheme ; ferroheme ; heme oxygenase-1 ; HO-1 enzyme ; HO1 ; HO2 ; HSP32 ; hemeoxygenase 1 ; Hemoglobin concentration result ; hemoglobin level ; Hemoglobin ; Hippocampus (Brain) ; Ammon Horn ; Cornu Ammonis ; Hippocampus ; hippocampal ; In Vitro ; Literature ; Mitochondria ; mitochondrial ; Mus ; Mice ; Mice Mammals ; Murine ; nervous system disorder ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; Nicotine ; Oxygenases ; Parkinson Disease ; Paralysis Agitans ; Parkinson ; Parkinson's disease ; Parkinsons disease ; Primary Parkinsonism ; Phosphorylation ; Protein Phosphorylation ; Purkinje Cells ; Purkinje's Corpuscles ; cerebellar Purkinje cell ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Research ; Research Personnel ; Investigators ; Researchers ; Risk ; Safety ; Seasons ; Stress ; Subarachnoid Hemorrhage ; Substantia nigra structure ; Substantia Nigra ; Family suidae ; Pigs ; Suidae ; Swine ; porcine ; suid ; Testing ; Tobacco ; Toxicology ; Toxin ; Tyrosine 3-Monooxygenase ; Tyrosine Hydroxylase ; Up-Regulation ; Upregulation ; cytokine ; Mediating ; Data Set ; Dataset ; improved ; Chronic ; Clinical ; Phase ; Neurologic ; Neurological ; Link ; Chemicals ; disability ; cigarette smoking ; cigarette use ; Neuroprotective Agents ; Neuroprotectants ; Neuroprotective Drugs ; Chemosensitization ; Chemosensitization/Potentiation ; Potentiation ; Phase II Clinical Trials ; Phase 2 Clinical Trials ; phase II protocol ; alpha synuclein ; NAC precursor ; PARK1 protein ; PARK4 protein ; SNCA ; SNCA protein ; a-syn ; a-synuclein ; alphaSP22 ; non A-beta component of AD amyloid ; non A4 component of amyloid precursor ; α-syn ; α-synuclein ; Therapeutic ; Fe element ; Iron ; Inflammatory ; Smoker ; Tobacco smoke ; Oral ; Inhalation Exposure ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; HO-2 protein ; heme oxygenase-2 ; brain cell ; experience ; nerve cell death ; nerve cell loss ; neuron cell death ; neuron cell loss ; neuron death ; neuronal cell death ; neuronal cell loss ; neuronal death ; neuronal loss ; neuron loss ; neuroprotection ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; novel ; disorder model ; Disease model ; Epidemiologic Research ; Epidemiologic Studies ; Epidemiological Studies ; Epidemiology Research ; epidemiologic investigation ; epidemiology study ; DA Neuron ; Dopamine neuron ; dopaminergic neuron ; Modeling ; Property ; response ; Early-Stage Clinical Trials ; Phase 1 Clinical Trials ; phase I protocol ; Phase I Clinical Trials ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; preventing ; prevent ; Dose ; DNA Alteration ; DNA mutation ; Genetic mutation ; Sequence Alteration ; genomic alteration ; DNA Sequence Alteration ; Data ; pre-clinical testing ; Preclinical Testing ; in vivo ; Apoptotic ; Rodent Model ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Pathologic ; Development ; developmental ; Pathway interactions ; pathway ; pre-clinical ; preclinical ; protective effect ; innovation ; innovate ; innovative ; volunteer ; mouse model ; murine model ; motor impairment ; movement impairment ; movement limitation ; therapeutic development ; therapeutic agent development ; overexpression ; overexpress ; treatment strategy ; preclinical safety ; pre-clinical safety ; Formulation ; improved outcome ; Inhalation ; Inhaling ; Genetic Diseases ; genetic condition ; genetic disorder ; pharmacokinetics and pharmacodynamics ; PK/PD ; MPTP mouse ; MPTP model ;

The goal of the proposed project is to evaluate the potential of HBI-002, a novel oral formulation of carbonmonoxide (CO), as a neuroprotective agent in Parkinson's disease (PD). A growing body of researchsuggests that low doses of CO - and the heme oxygenase (HO) enzymes that generate endogenous CO -protect against neuronal cell loss in PD, and epidemiologic studies have associated cigarette smoking with alower risk of PD. Together, these observations suggest that low doses of CO may be neuroprotective in PD.Nicotine does not appear to underlie the protective effect of tobacco, as a clinical study of nicotine in PD didnot show significant improvement. At low levels (<10% CO-hemoglobin [COHb]), such as found in smokers,CO has been shown to have marked anti-apoptotic, anti-oxidant, and anti-inflammatory properties, and it hasbecome a promising therapeutic under study for multiple neurologic and non-neurologic diseases. CO isgenerated by heme oxygenase 1 (HO-1) and 2 (HO-2), which transform the toxic species heme into CO,biliverdin, and iron. Converging evidence links the function of HO-1 and HO-2 to neuroprotection in PD, andthe literature indicates that CO is protective in a PD model.The clinical safety and tolerability of CO at levels up to 13.9% COHb has been demonstrated in 25 Phase 1and Phase 2 clinical trials (not in PD, but including in subarachnoid hemorrhage) using a variety of forms of COadministration, and there are ongoing clinical studies with CO. The absence of toxicity of CO at low COHblevels has been well demonstrated in the literature, providing supportive safety data for the COHb levels underconsideration for PD. However, barriers to chronic dosing of CO with prior therapeutic administrativeapproaches have prevented the development of a CO therapeutic for chronic use, as would be the case in PD.HBI-002, a novel oral CO drug product, is being developed for the treatment of PD. The administration of adefined dose of CO delivered by oral administration of HBI-002 enables further development of CO as atherapeutic while obviating the problems associated with previously studied CO administration strategies,including, for inhaled CO, accidental inhalation exposure due to the need for compressed CO cylinders andimprecise dosing, and, for carrier molecule-bound CO (CORMs), toxicological concerns with carrier molecules.Pharmacokinetic and pharmacodynamic studies in mice, rats, pigs, and dogs with oral HBI-002 havedemonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development, aspresented in this proposal, is to confirm the neuroprotective potential of HBI-002 in animal models of PD and tobetter understand the mechanisms of neuroprotection. For this purpose, we will assess the efficacy of HBI-002in multiple in vivo PD models in two different species. In these models we will assess HBI-002 rescue of striataldopamine loss, substantia nigra dopamine cell loss, and motor impairment; and we will explore the impact ofHBI-002 on inflammatory cascades, Nrf-2 and HO-1 pathways, and mitochondrial biogenesis.

Public Health Relevance Statement:
PROJECT NARRATIVE This application aims to evaluate whether HBI-002, an oral carbon monoxide (CO) therapeutic, can improve outcomes in rodent models of Parkinson's disease (PD). If successful, this research will provide critical proof- of-concept for further development of HBI-002 in PD to prevent the progression of this devastating disease.

Project Terms:
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