Method of identifying and treating premature infants at risk for BPD
Inventors
Greene, Douglas Stuart • Medicis, Joseph J. • Potenziano, Jim
Assignees
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Publication Number
US-12007399-B2
Publication Date
2024-06-11
Expiration Date
Abstract
Methods for identifying premature infants at risk for developing bronchopulmonary dysplasia and/or most likely to benefit from administration of inhaled nitric oxide for prevention of bronchopulmonary dysplasia (BPD). Methods for treating premature infants identified as at risk and/or likely to benefit are provided. also provided are methods for identifying premature infants that are not at risk for developing bronchopulmonary dysplasia and/or unlikely to benefit from administration of inhaled nitric oxide for prevention of bronchopulmonary dysplasia, and methods for avoiding risks of toxicity and undesirable side effects associated with inhaled nitric oxide therapy comprising administering only non-iNO treatment modalities to these infants.
Core Innovation
The described invention relates to stratifying a premature infant, less than 30 weeks gestational age, at risk for developing bronchopulmonary dysplasia by using biomarkers predictive of risk and therapeutic response to inhaled nitric oxide. The approach includes obtaining a blood or tissue sample prior to initiation of inhaled nitric oxide therapy and analyzing the sample for genetic mutations in a gene encoding a nitric oxide synthase, including endothelial nitric oxide synthase variants, that result in decreased endogenous synthesis of nitric oxide.
The described invention also incorporates physiologic biomarker measurements used to guide whether inhaled nitric oxide is given or avoided. The method tests plasma total concentration of nitrate and nitrite and concentration of nitric oxide in exhaled ambient air or nitric oxide-free air, and uses specified comparisons of these biomarker values together with the presence or absence of an eNOS genetic mutation to select non-inhaled nitric oxide modalities versus inhaled nitric oxide.
In addition, the description relates patient subgroup variability in treatment efficacy to biomarker profiles that differ across infants. It provides genetic mutation examples in an endothelial nitric oxide synthase gene, including T-786C and G894T variants, and supports selecting inhaled nitric oxide for infants predicted to benefit and using non-iNO modalities for infants predicted not to benefit, with the stated goal of reducing risks associated with administration of inhaled nitric oxide.
Claims Coverage
The partial content identifies two independent claims. Together, they cover decision-making for premature infants less than 30 weeks gestational age using eNOS-decreasing mutation status, and in one claim additional plasma nitrate/nitrite and exhaled nitric oxide thresholds, to choose between inhaled nitric oxide and non-inhaled nitric oxide modalities.
Genotype-guided iNO responder identification in preterm infants
Obtaining a blood or tissue sample prior to initiation of inhaled nitric oxide therapy; analyzing the sample for a genetic mutation in a gene encoding a nitric oxide synthase that results in decreased endogenous synthesis of nitric oxide; determining whether the genetic mutation is present or absent, wherein presence indicates the premature infant is likely to have a reduction in the likelihood of developing bronchopulmonary dysplasia when treated with inhaled nitric oxide; and treating with inhaled nitric oxide when the genetic mutation is present, wherein the premature infant is less than 30 weeks gestational age.
Biomarker-threshold selection to avoid iNO risks in preterm infants
Testing the premature infant for plasma total concentration of nitrate and nitrite, concentration of nitric oxide in exhaled ambient or nitric oxide-free air, and presence of a genetic mutation in the eNOS gene in a blood or tissue sample that results in decrease endogenous synthesis of nitric oxide; determining whether the total concentration of nitrate and nitrite is at least about 50 μM and/or the exhaled nitric oxide concentration is about 2.5 ppb or higher and/or no genetic mutation is present; treating with non-inhaled nitric oxide modalities only if the criteria are met; and treating with inhaled nitric oxide to reduce the likelihood of developing bronchopulmonary dysplasia when the total concentration of nitrate and nitrite is less than about 50 μM, when the exhaled nitric oxide concentration is less than about 1.5 ppb, and/or when the genetic mutation is present, wherein the premature infant is less than 30 weeks gestational age.
Across the independent claims, the key inventive coverage is decision-making for premature infants using nitric oxide synthase/eNOS genetic mutation status and, in the risk-avoidance method, additional biomarker thresholds from plasma nitrate/nitrite and exhaled nitric oxide to choose between inhaled nitric oxide and non-inhaled nitric oxide modalities.
Stated Advantages
Reduce the likelihood of developing bronchopulmonary dysplasia by selecting appropriate nitric oxide modality based on predictive biomarkers and eNOS mutation status.
Avoid risks associated with administration of inhaled nitric oxide to premature infants at risk for developing bronchopulmonary dysplasia.
Documented Applications
A clinical decision method for stratifying and treating premature infants less than 30 weeks gestational age to reduce the likelihood of bronchopulmonary dysplasia, including identifying likely responders to inhaled nitric oxide and avoiding risks by selecting non-inhaled nitric oxide modalities when indicated.
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