Methods to improve organ viability
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Publication Number
US-12285008-B2
Publication Date
2025-04-29
Expiration Date
Abstract
The present disclosure provides methods to improve the viability of an organ, or organs, by continuously administering a composition comprising NOx gas directly to the organ(s).
Core Innovation
The invention provides methods for improving organ viability in organs with ischemia-reperfusion damage by continuously administering a composition comprising 20 ppm or less of NO gas directly to the organ. The NO gas is administered continuously and directly to the organ, and the approach is evaluated against a control organ that has not been contacted with the composition.
In one aspect, the method increases manganese-dependent superoxide dismutase (SOD2 or MnSOD) activity in the organ compared to the control organ. In another aspect, the method inhibits formation of nitrotyrosine adduct formation in the organ compared to the control organ. In further aspects, the method prevents inactivation of mitochondrial complex I activity, complex II activity, complex III activity, and/or complex IV activity compared to the control organ.
The composition includes nitrogen oxides (NOx), preferably gaseous nitric oxide, administered directly to organs via organ perfusion systems or ventilation, including continuous administration during transplant-relevant workflows. Example formulations discussed include gas versus liquid concepts and perfusion fluids, including acellular Steen solution, optionally with sodium caprylate, N-acetyl-DL-tryptophan, and human albumin.
Claims Coverage
The partial content includes three independent claims, each focused on a distinct inventive endpoint measured against a control organ not contacted with the NO gas composition, with a shared core requirement of continuous direct administration of a composition comprising 20 ppm or less of NO gas.
Continuous direct administration of 20 ppm or less NO gas to increase MnSOD activity
Continuously administering a composition comprising 20 ppm or less of NO gas directly to the organ to increase MnSOD (SOD2) activity compared to a control organ that has not been contacted with the composition.
Continuous direct administration of 20 ppm or less NO gas to inhibit nitrotyrosine formation
Continuously administering a composition comprising 20 ppm or less of NO gas directly to the organ to inhibit formation of nitrotyrosine adduct compared to a control organ that has not been contacted with the composition.
Continuous direct administration of 20 ppm or less NO gas to prevent mitochondrial complex inactivation
Continuously administering a composition comprising 20 ppm or less of NO gas directly to the organ to prevent inactivation of mitochondrial complex I activity, complex II activity, complex III activity, complex IV activity, or a combination thereof compared to a control organ.
Across the independent claims, the coverage centers on continuous, direct delivery of NO gas at 20 ppm or less to achieve increased MnSOD activity, inhibited nitrotyrosine adduct formation, and/or prevention of inactivation of one or more mitochondrial respiratory complexes versus a control organ not contacted with the composition.
Stated Advantages
Increases manganese-dependent superoxide dismutase (SOD2 or MnSOD) activity in an organ with ischemia-reperfusion damage.
Inhibits formation of nitrotyrosine adduct in an organ with ischemia-reperfusion damage.
Prevents inactivation of mitochondrial complex I activity, complex II activity, complex III activity, complex IV activity, or a combination thereof in an organ with ischemia-reperfusion damage.
Documented Applications
EVLP lung study protocol with gaseous nitric oxide (gNO) arms for ischemia-reperfusion-related organ viability evaluation.
In vivo pediatric swine cardiac arrest/asphyxial model where 20 ppm NO during CPR and post-ROSC improved cerebral mitochondrial metrics, including increased cortical/hippocampal respiratory control ratio (RCR) and decreased mitochondrial reactive oxygen species (mtROS).
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