RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome

Urak, Kevin T.; Blanco, Giselle N.; Shubham, Shambhavi; Lin, Leou-Chyr; Dassie, Justin P.; Thiel, William H.; Chen, Yani; Sonkar, Vijay K.; Lei, Beilei; Murthy, Shubha; Gutierrez, Wade R.; Wilson, Mary E.; Stiber, Jonathan A.; Klesney-Tait, Julia; Dayal, Sanjana; Miller, Francis J.; Giangrande, Paloma H.

doi:10.1038/s41467-018-08030-y

Cited by 16 publications

(14 citation statements)

References 65 publications

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“…There is now evidence being accumulated that an aptamer-based therapeutic approach directed specifically against histones could potentially reverse some of the clinical findings seen in histone mediated diseases [41] . Recently, molecular medications such as nuclease-resistant RNA aptamers have been used in experimental MODS to bind with high affinity and specificity to human histones H3 and H4 implicated in MODS [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Gene expression signatures identify paediatric patients with multiple organ dysfunction who require advanced life support in the intensive care unit

et al. 2020

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Background: Multiple organ dysfunction syndrome (MODS) occurs in the setting of a variety of pathologies including infection and trauma. Some patients decompensate and require Veno-Arterial extra corporeal membrane oxygenation (ECMO) as a palliating manoeuvre for recovery of cardiopulmonary function. The molecular mechanisms driving progression from MODS to cardiopulmonary collapse remain incompletely understood, and no biomarkers have been defined to identify those MODS patients at highest risk for progression to requiring ECMO support. Methods: Whole blood RNA-seq profiling was performed for 23 MODS patients at three time points during their ICU stay (at diagnosis of MODS, 72 hours after, and 8 days later), as well as four healthy controls undergoing routine sedation. Of the 23 MODS patients, six required ECMO support (ECMO patients). The predictive power of conventional demographic and clinical features was quantified for differentiating the MODS and ECMO patients. We then compared the performance of markers derived from transcriptomic profiling including [1] transcriptomically imputed leukocyte subtype distribution, [2] relevant published gene signatures and [3] a novel differential gene expression signature computed from our data set. The predictive power of our novel gene expression signature was then validated using independently published datasets. Finding: None of the five demographic characteristics and 14 clinical features, including The Paediatric Logistic Organ Dysfunction (PELOD) score, could predict deterioration of MODS to ECMO at baseline. From previously published sepsis signatures, only the signatures positively associated with patient's mortality could differentiate ECMO patients from MODS patients, when applied to our transcriptomic dataset (P-value ranges from 0.01 to 0.04, Student's test). Deconvolution of bulk RNA-Seq samples suggested that lower neutrophil counts were associated with increased risk of progression from MODS to ECMO (P-value = 0.03, logistic regression, OR=2.82 [95% CI 0.63-12.45]). A total of 30 genes were differentially expressed between ECMO and MODS patients at baseline (log2 fold change 1 or-1 with false discovery rate 0.01). These genes are involved in protein maintenance and epigenetic-related processes. Further univariate analysis of these 30 genes suggested a signature of seven DE genes associated with ECMO (OR > 3.0, P-value 0.05, logistic regression). Notably, this contains a set of histone marker genes, including H1F0, HIST2H3C, HIST1H2AI, HIST1H4, HIST1H2BL and HIST1H1B, that were highly expressed in ECMO. A risk score derived from expression of these genes differentiated ECMO and MODS patients in our dataset (AUC = 0.91, 95% CI 0.79-1.00, Pvalue = 7e-04, logistic regression) as well as validation dataset (AUC= 0.73, 95% CI 0.53-0.93, P-value = 2e-02, logistic regression).

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Section: Discussionmentioning

confidence: 99%

Gene expression signatures identify paediatric patients with multiple organ dysfunction who require advanced life support in the intensive care unit

et al. 2020

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“…In preclinical models and in vitro, inhibition of NET formation may be a promising option for therapeutic intervention. 51–53 …”

Section: Coagulation and Sepsismentioning

confidence: 99%

Enigmatic role of coagulopathy among sepsis survivors: a review of coagulation abnormalities and their possible link to chronic critical illness

Winer

Salyer

Beckmann

et al. 2020

Trauma Surg Acute Care Open

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There are sparse clinical data addressing the persistence of disordered coagulation in sepsis and its role in chronic critical illness. Coagulopathy in the absence of anticoagulant therapy and/or liver disease can be highly variable in sepsis, but it tends to be prolonged in patients in the intensive care unit with a length of stay greater than 14 days. These coagulation abnormalities tend to precede multisystem organ failure and persistence of these coagulation derangements can predict 28-day mortality. The studies evaluated in this review consistently link sepsis-associated coagulopathy to poor long-term outcomes and indicate that disordered coagulation is associated with unfavorable outcomes in chronic critical illness. However, the causative mechanism and the definitive link remain unclear. Longer follow-up and more granular data will be required to fully understand coagulopathy in the context of chronic critical illness.

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“…Thus, with the aim of finding a specific anti-histone therapy, in a previous study, the authors selected and characterized RNA aptamers against histones. 2 One of these aptamers, HBA7 (previously named KU7) has been used by Lei et al. 1 to demonstrate its efficacy in two animal models, neutralizing histones injury when co-administered and in a model of ALI from inhaling wood smoke particulate, where HBA7 alleviates lung injury.…”

Section: Main Textmentioning

confidence: 99%

Inhaled aptamer therapy: A hopeful therapy for lung disease

Martín

2023

Molecular Therapy - Nucleic Acids

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RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome

Cited by 16 publications

References 65 publications

Gene expression signatures identify paediatric patients with multiple organ dysfunction who require advanced life support in the intensive care unit

Gene expression signatures identify paediatric patients with multiple organ dysfunction who require advanced life support in the intensive care unit

Enigmatic role of coagulopathy among sepsis survivors: a review of coagulation abnormalities and their possible link to chronic critical illness

Inhaled aptamer therapy: A hopeful therapy for lung disease

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