Document text
Principal Investigator: David Jackson
Organization: CERIA THERAPEUTICS, INC.
Fiscal Year: 2024
Award: $1,216,721
Funding agency: National Heart Lung and Blood Institute
SUMMARY
Acute respiratory distress syndrome (ARDS) accounts for 10% of ICU admissions worldwide, with a mortality
as high as 46%. ARDS incidence has risen dramatically during the COVID-19 pandemic. Despite improvements
in critical care and early detection of lung injury, the management of ARDS remains largely supportive. Although
mechanical ventilation may provide the necessary life support, impaired pulmonary mechanics and subsequent
ventilator induced lung injury (VILI) can impose a second insult that worsens outcomes. A range of insults,
including trauma, sepsis, pulmonary infections, or toxin exposure, are associated with acute lung injury (ALI) and
the subsequent development of a systemic inflammatory response and progression to ARDS, leading to
alterations in lung compliance and lung fibrosis. A central pathogenic feature of ARDS is the persistent activation
of inflammation and oxidative stress. Following ALI, lung macrophages produce pro-inflammatory cytokines that
result in the recruitment of additional inflammatory cells and the generation of reactive oxygen species (ROS).
Persistent amplification of inflammation and oxidative stress leads to the progression to ARDS, promotion of
long-term fibrosis and morbidity.
Ceria Therapeutics is developing a novel therapeutic product, CTX-002, that synergistically targets both
inflammation and oxidative stress. CTX-002 (CNP-miR146a) is a cerium oxide nanoparticle (CNP), which
possess ROS scavenging properties, conjugated with an anti-inflammatory miR146a mimetic to target both ROS
and the inflammatory response. Supported by a Phase I application, we have demonstrated that a single
administration of CTX-002 can prevent bleomycin, MRSA, and lipopolysaccharide-induced inflammation and
lung injury, even when administered three or seven days after injury. In addition, treatment with CTX-002 resulted
in improved pulmonary mechanics and prevention of subsequent VILI. We also demonstrated that systemic
intravenous single and repeat-dose administration of up to 10-fold the intended clinical dose of CTX-002 showed
no signs of toxicity in rats. The objectives of this Phase II proposal are to 1) determine pulmonary distribution of
CTX-002 in pigs to demonstrate that intratracheal administration of the drug results in no systemic exposure of
CTX-002 but increased concentration in the lungs; 2) scale-up synthesis and complete analytical
characterization, formulation and stability of CTX-002; 3) perform GLP-compliant safety and toxicology studies
in rats and pigs. To complete this Phase II application, we will prepare and submit an IND for clearance to begin
first-in-human clinical trials of CTX-002 for ARDS.
Terms: <3-10C><AMCF-I><ARDS><Abdomen><Active Oxygen><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Admission><Admission activity><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Adverse effects><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Assay><Award><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bioassay><Biological Assay><Bis(beta-chloroethyl) Sulfide><Bleo><Bleomycin><Body Tissues><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><CTX><CXCL8><CYCLO-cell><Carloxan><Causality><Ce element><Cell Body><Cells><Cerium><Cessation of life><Chemical Exposure><Chemistry><Ciclofosfamida><Ciclofosfamide><Cicloxal><Clafen><Claphene><Clinical><Clinical Trials><Collaborations><Common Rat Strains><Critical Care><Cycloblastin><Cycloblastine><Cyclophospham><Cyclophosphamide><Cyclophosphamidum><Cyclophosphan><Cyclophosphane><Cyclophosphanum><Cyclostin><Cyclostine><Cytophosphan><Cytophosphane><Cytoxan><Da Nang Lung><Death><Development><Di-2-chloroethyl Sulfide><Dichlorodiethyl Sulfide><Dose><Drug Kinetics><Drugs><Early Diagnosis><Endoxan><Endoxana><Enduxan><Etiology><Failure><Family suidae><Feedback><Fibrosis><Formulation><Fosfaseron><GCP1><Gases><Generations><Genoxal><Genuxal><Goals><HPGF><Hepatocyte-Stimulating Factor><Hospital Mortality><Hour><Hybridoma Growth Factor><ICP-MS><IFN-beta 2><IFNB2><IL-6><IL-8><IL6 Protein><IL8><IL8 gene><Impairment><In-house Mortalities><Incidence><Inductively Coupled Plasma Mass Spectrometry><Inflammation><Inflammatory><Inflammatory Response><Inhalation><Inhaling><Inhospital Mortality><Injury><Interleukin-6><Intravenous><K60><Laboratories><Ledoxina><Life><Lipopolysaccharides><Lung><Lung Compliance><Lung Respiratory System><Lung Tissue Fibrosis><Lung damage><Lung infections><MGI-2><MRSA><Macrophage><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Measures><Mechanical ventilation><Mechanics><Medication><Methicillin Resistant S. Aureus><Micro RNA><MicroRNAs><Miniature Swine><Minipigs><Mitoxan><Modeling><Molecular><Morbidity><Morbidity - disease rate><Mustard Gas><Myeloid Differentiation-Inducing Protein><Mφ><NHLBI><National Heart, Lung, and Blood Institute><Neosar><Nuclear><Operative Procedures><Operative Surgical Procedures><Organ><Outcome><Oxidative Stress><Oxygen Radicals><Particle Size><Pathogenesis><Pathogenicity><Patients><Pharmaceutical Preparations><Pharmacokinetics><Pharmacological Treatment><Phase><Pigs><Pilot Projects><Plasmacytoma Growth Factor><Poison><Pre IND FDA meeting><Pre-IND mtg><Preparation><Prevention><Pro-Oxidants><Process><Procytox><Production><Property><Pulmonary Body System><Pulmonary Fibrosis><Pulmonary Organ System><Rat><Rats Mammals><Rattus><Reactive Oxygen Species><Recommendation><Recovery><Research><Respiratory System><Respiratory Tracts><Respiratory tract structure><Rodent><Rodentia><Rodents Mammals><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SBIR><SCYB8><Safety><Sendoxan><Sepsis><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Shock Lung><Small Business Innovation Research><Small Business Innovation Research Grant><Stiff lung><Suidae><Sulfur Mustard><Surgical><Surgical Interventions><Surgical Procedure><Swine><Syklofosfamid><TSG-1><Therapeutic><Tissues><Toxic Chemical><Toxic Substance><Toxic effect><Toxicities><Toxicology><Toxin><Trauma><Ventilator-induced lung injury><Yellow Cross Liquid><Yperite><Zytoxan><b-ENAP><blood infection><bloodstream infection><causation><cerium oxide nano particle><cerium oxide nanoparticle><compare to control><comparison control><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cytokine><developmental><disease causation><drug/agent><early detection><fibrosis in the lung><first in man><first-in-human><improved><injuries><interferon beta 2><intravenous administration><lung fibrosis><lung function><lung injury><manufacture><mechanic><mechanical><mechanical respiratory assist><mechanically ventilated><methicillin resistance Staphylococcus aureus><methicillin resistant Staphylococcus aureus><methicillin resistant strains of Staphylococcus aureus><miRNA><miRNAs><mimetics><mini pig><mini-swine><miniswine><mortality><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><phase 2 study><phase II study><pilot study><porcine><pre-IND consultation><pre-IND discussion><pre-IND meeting><pre-Investigational New Drug meeting><preparations><prevent><preventing><pulmonary><pulmonary damage><pulmonary function><pulmonary infections><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><recruit><scale up><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><side effect><suid><supplemental oxygen><surgery><systemic inflammation><systemic inflammatory response><toxic compound><ventilation induced lung injury><ventilator associated lung injury><wet lung>