Sepsis and related multiple organ dysfunction are a major cause of mortality and morbidity, responsible for over 215 000 deaths per year in the US. Despite growing understanding of the pathomechanism of sepsis, treatment options are still limited primarily to antibiotics, glucocorticoids, and supportive measures. There is wide consensus that mitochondrial dysfunction, so called cytopathic hypoxia, develops over the course of sepsis, and becomes the defining feature of the late stage of the process. Cytopathic hypoxia is characterized by a reversible suppression of mitochondrial complex I, ATP production and oxygen consumption which result in immunosuppression and widespread organ failure. Experimental manipulations, such as overexpression of transcription factors that enhance mitochondrial biogenesis (e.g. the mitochondrial transcription factor A, TFAM), have been found effective in models of sepsis but clinical applications are hampered by lack of suitably powerful pharmacological biogenesis stimulators. Gencia developed a recombinant form of human TFAM (rhTFAM), modified to allow it to traverse cellular barriers and to be specifically imported into mitochondria. After being injected rhTFAM enters mitochondria in all tissues examined so far and acts as a transcription factor, rapidly (within hours) increasing complex I activity, oxygen consumption, mitochondrial mass and maximum ATP output by up to 150%, while decreasing ROS production. The magnitude, speed and persistence of mitochondrial biogenesis stimulation achieved with rhTFAM are larger than with any pharmacological agents described in the literature. Behaviorally, healthy mice treated with rhTFAM increased running endurance (rotarod latency) by 300%, and there were no significant side-effects over up to 10 months of dosing even in mice aged 34 months. Preliminary LPS sepsis animal model experiments show significantly improved survival in mice treated with rhTFAM. In this Phase I SBIR project we will test whether rhTFAM is capable of reversing of the cytopathic hypoxia observed in an LPS model of sepsis. Specific aims of the project are: 1) Determine if rhTFAM treatment ameliorates inflammation, mitochondrial function, and cell death in HepG2 and human primary liver cells challenged with LPS 2) Determine whether rhTFAM treatment alters mortality in c57/bl6 mice challenged with LPS. Confirmation of a beneficial effect of rhTFAM in LPS models of sepsis would pave the way for Phase II SBIR work where rhTFAM would be used in the CLP (cecal ligation and puncture) model of sepsis.
Public Health Relevance: The aims carried out under this proposal will show feasibility for rhTFAM as a treatment for Sepsis. Sepsis is a systemic inflammatory response to infection and other severe stressors, and is the leading cause of death in the ICU setting, responsible for 215,000 fatalities per year in the US. Despite growing understanding of the pathomechanism of sepsis, treatment options are still limited primarily to antibiotics, glucocorticoids, and supportive measures.
Thesaurus Terms: "adverse Effects; Animal Model; Animal Models And Related Studies; Antibiotic Agents; Antibiotic Drugs; Antibiotics; Biogenesis; Body Tissues; Cause Of Death; Cell Death; Cessation Of Life; Closure By Ligation; Complex; Consensus; Death; Dose; Dysfunction; Functional Disorder; Glucocorticoids; Hepatic Cells; Hepatic Parenchymal Cell; Hepatocyte; Hour; Human; Human, General; Hypoxia; Hypoxic; Inflm; Immunosuppression Effect; Immunosuppressions (Physiology); Immunosuppressive Effect; Infection; Inflammation; Inflammatory Response; Ligation; Literature; Liver Cells; Mammals, Mice; Man (Taxonomy); Man, Modern; Measures; Mice; Miscellaneous Antibiotic; Mitochondria; Modeling; Morbidity; Morbidity - Disease Rate; Mortality; Mortality Vital Statistics; Murine; Mus; Natural Immunosuppression; Organ; Organ Failure; Origin Of Life; Output; Oxygen Consumption; Oxygen Deficiency; Phase; Physiopathology; Process; Production; Proteins; Puncture Procedure; Punctures; Recombinants; Running; Sbir; Sbirs (R43/44); Sepsis; Small Business Innovation Research; Small Business Innovation Research Grant; Speed; Speed (Motion); Staging; Testing; Therapeutic Glucocorticoid; Tissues; Treatment Side Effects; Work; Aged; Bloodstream Infection; Clinical Applicability; Clinical Application; Experiment; Experimental Research; Experimental Study; Gene Product; Immunosuppression; Improved; Mitochondrial; Mitochondrial Dysfunction; Mitochondrial Transcription Factor A; Model Organism; Mttf1 Mitochondrial Transcription Factor 1; Mttf1 Transcription Factor; Necrocytosis; Overexpression; Pathophysiology; Public Health Relevance; Research Study; Side Effect; Stressor; Therapy Adverse Effect; Transcription Factor; Treatment Adverse Effect"
