Gene expression signatures useful to predict or diagnose sepsis and methods of using the same
Inventors
Tsalik, Ephraim L. • Ginsburg, Geoffrey S. • Woods, Christopher W. • Giraldo, Ricardo Henao • MYERS, Rachel A.
Assignees
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Publication Number
US-12071668-B2
Publication Date
2024-08-27
Expiration Date
2038-01-16
Abstract
The present disclosure provides methods for determining whether a subject has sepsis, or is at risk of developing sepsis, and methods of treating the subject based on the determination. Also provided are methods for determining an increased risk of mortality in a subject with sepsis or suspected of having sepsis, and methods of treating the subject based on the determination. Systems useful for the same are also provided.
Core Innovation
The invention provides methods for determining whether a subject has sepsis or is at risk of developing sepsis, as well as methods of treating the subject based on such determinations. Additionally, it offers methods for determining an increased risk of mortality in subjects with sepsis or suspected sepsis, and corresponding treatment methods. Systems useful for performing these determinations are also disclosed.
The invention addresses the problem that current tools for diagnosing and stratifying sepsis patients lack molecular specificity and do not adequately quantify the patient's dysregulated host response to infection. Clinical severity scores and available assays reflect general illness severity but fail to enable personalized treatment or accurate prognosis, leading to unmet needs in improved risk stratification and prognosis, and the failure of sepsis-specific therapies to succeed in clinical practice.
Claims Coverage
The patent discloses three main inventive features covering methods of diagnosing sepsis, determining mortality risk in sepsis, and treating sepsis based on gene expression signatures. These features include the associated platforms and the gene sets used for these determinations.
Method of determining sepsis or risk of sepsis by measuring differential gene expression
A method comprising providing a biological sample and measuring on a platform the mRNA levels of a pre-defined set of genes (including PCBP1, TMBIM6, LASP1, KLF2, OS9, APMAP, CD14, NAMPT, NQO2, CDK5RAP2, SIGLEC10, TSC22D3, RCN3, LST1, HBA1, FGR, TYMP, ATG16L2, CEACAM4, PECAM1, HMHA1, APOBEC3A, and P2RX1). The subject is identified as having sepsis or risk thereof when there is an increase in expression of three or more genes from the first subset and a decrease in expression of three or more genes from the second subset, as compared to uninfected controls.
Method of determining increased risk of mortality in sepsis via gene expression profiling
A method comprising providing a biological sample and measuring differential expression of a pre-defined set of genes, characterized by increased expression of one or more genes selected from TRIB1, CKS2, MKI67, POLD3, PLK1, and/or decreased expression of two or more genes selected from TGFBI, LY86, CST3, CBFA2T3, RCBTB2, TST, CX3CR1, CD5, MTMR11, CLEC10A, EMR3, DHRS7B, and CEACAM8, with the subject identified as having increased mortality risk when such patterns are present.
Methods of treating sepsis and systems for gene expression-based sepsis diagnostics and prognostics
Methods of treating subjects for sepsis or increased mortality risk by administering an appropriate treatment regimen based on gene expression determinations. Systems comprising processors, sample input and analysis circuits, storage circuits, and memory with computer code configured to measure gene expression levels of pre-defined gene sets, normalize them, retrieve weighting coefficients, calculate probabilities of sepsis or mortality, and output determinations. The platform can include array, thermal cycler, hybridization detector, nucleic acid mass spectrometry, sequencing platforms, or combinations thereof.
The claims cover comprehensive gene expression-based diagnostic and prognostic methods for sepsis and mortality risk determination, associated treatment methods, and system embodiments implementing these methods via pre-defined gene sets and various platform technologies.
Stated Advantages
Improved accuracy in sepsis prognosis enabling appropriate matching of patients with resources.
Molecular phenotyping allowing better patient selection and prognostic enrichment for clinical trials.
Quantitative diagnosis of sepsis distinct from non-septic acute infections.
Potential to improve clinical care through personalized treatment and risk stratification.
Documented Applications
Determining whether a subject has sepsis or is at risk of developing sepsis, including ventilator associated pneumonia.
Determining increased risk of mortality in a subject with sepsis or suspected sepsis.
Methods of treating sepsis or increased risk of mortality based on gene expression determinations, including administering antibiotics, hydration, blood transfusion, vasopressors, and ventilator assistance.
Systems and platforms for gene expression-based sepsis diagnosis, prognosis, and treatment decision-making.
Use of transcriptomic signatures detected at or before onset of infection for stratifying sepsis severity and guiding clinical management.
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