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A novel C5a-neutralizing mirror-image (l-)aptamer prevents organ failure and improves survival in experimental sepsis.

ABSTRACT: Complement factor C5a is a potent proinflammatory mediator that contributes to the pathogenesis of numerous inflammatory diseases. Here, we describe the discovery of NOX-D20, a PEGylated biostable mirror-image mixed (l-)RNA/DNA aptamer (Spiegelmer) that binds to mouse and human C5a with picomolar affinity. In vitro, NOX-D20 inhibited C5a-induced chemotaxis of a CD88-expressing cell line and efficiently antagonized the activation of primary human polymorphonuclear leukocytes (PMN) by C5a. Binding of NOX-D20 to the C5a moiety of human C5 did not interfere with the formation of the terminal membrane attack complex (MAC). In sepsis, for which a specific interventional therapy is currently lacking, complement activation and elevated levels of C5a are suggested to contribute to multiorgan failure and mortality. In the model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), NOX-D20 attenuated inflammation and organ damage, prevented the breakdown of the vascular endothelial barrier, and improved survival. Our study suggests NOX-D20 as a new therapeutic candidate for the treatment of sepsis.

SUBMITTER: Hoehlig K

PROVIDER: S-EPMC3863792 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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A novel C5a-neutralizing mirror-image (l-)aptamer prevents organ failure and improves survival in experimental sepsis.

Hoehlig Kai K Maasch Christian C Shushakova Nelli N Buchner Klaus K Huber-Lang Markus M Purschke Werner G WG Vater Axel A Klussmann Sven S

Molecular therapy : the journal of the American Society of Gene Therapy 20130726 12

Complement factor C5a is a potent proinflammatory mediator that contributes to the pathogenesis of numerous inflammatory diseases. Here, we describe the discovery of NOX-D20, a PEGylated biostable mirror-image mixed (l-)RNA/DNA aptamer (Spiegelmer) that binds to mouse and human C5a with picomolar affinity. In vitro, NOX-D20 inhibited C5a-induced chemotaxis of a CD88-expressing cell line and efficiently antagonized the activation of primary human polymorphonuclear leukocytes (PMN) by C5a. Binding ...[more]

PMID: 23887360

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Project description:BACKGROUND: Gnosis is a modality-specific ability to access semantic knowledge of an object or stimulus in the presence of normal perception. Failure of this is agnosia or disorder of recognition. It can be highly selective within a mode. self-images are different from others as none has seen one's own image except in reflection. Failure to recognize this image can be labeled as mirror image agnosia or Prosopagnosia for reflected self-image. Whereas mirror agnosia is a well-recognized situation where the person while looking at reflected images of other objects in the mirror he imagines that the objects are in fact inside the mirror and not outside. MATERIAL AND METHODS: Five patients, four females, and one male presented with failure to recognize reflected self-image, resulting in patients conversing with the image as a friend, fighting because the person in mirror is wearing her nose stud, suspecting the reflected self-image to be an intruder; but did not have prosopagnosia for others faces, non living objects on self and also apraxias except dressing apraxia in one patient. This phenomena is new to our knowledge. RESULTS: Mirror image agnosia is an unique phenomena which is seen in patients with parietal lobe atrophy without specificity to a category of dementing illness and seems to disappear as disease advances. DISCUSSION: Reflected self-images probably have a specific neural substrate that gets affected very early in posterior dementias specially the ones which predominantly affect the right side. At that phase most patients are mistaken as suffering from psychiatric disorder as cognition is moderately preserved. As disease becomes more widespread this symptom becomes masked. A high degree of suspicion and proper assessment might help physicians to recognize the organic cause of the symptom so that early therapeutic interventions can be initiated. Further assessment of the symptom with FMRI and PET scan is likely to solve the mystery of how brain handles reflected self-images. CONCLUSION: A new observation involving failure to recognize reflected self-images is reported.

Project description:ObjectivesSepsis-3 defines organ dysfunction as an increase in the Sequential Organ Failure Assessment score by greater than or equal to 2 points. However, some Sequential Organ Failure Assessment score components are not routinely recorded in all hospitals' electronic health record systems, limiting its utility for wide-scale sepsis surveillance. The Centers for Disease Control and Prevention recently released the Adult Sepsis Event surveillance definition that includes simplified organ dysfunction criteria optimized for electronic health records (eSOFA). We compared eSOFA versus Sequential Organ Failure Assessment with regard to sepsis prevalence, overlap, and outcomes.DesignRetrospective cohort study.SettingOne hundred eleven U.S. hospitals in the Cerner HealthFacts dataset.PatientsAdults hospitalized in 2013-2015.InterventionsNone.Measurements and main resultsWe identified clinical indicators of presumed infection (blood cultures and antibiotics) concurrent with either: 1) an increase in Sequential Organ Failure Assessment score by 2 or more points (Sepsis-3) or 2) 1 or more eSOFA criteria: vasopressor initiation, mechanical ventilation initiation, lactate greater than or equal to 2.0 mmol/L, doubling in creatinine, doubling in bilirubin to greater than or equal to 2.0 mg/dL, or greater than or equal to 50% decrease in platelet count to less than 100 cells/μL (Centers for Disease Control and Prevention Adult Sepsis Event). We compared area under the receiver operating characteristic curves for discriminating in-hospital mortality, adjusting for baseline characteristics. Of 942,360 patients in the cohort, 57,242 (6.1%) had sepsis by Sequential Organ Failure Assessment versus 41,618 (4.4%) by eSOFA. Agreement between sepsis by Sequential Organ Failure Assessment and eSOFA was good (Cronbach's alpha 0.81). Baseline characteristics and infectious diagnoses were similar, but mortality was higher with eSOFA (17.1%) versus Sequential Organ Failure Assessment (14.4%; p < 0.001) as was discrimination for mortality (area under the receiver operating characteristic curve, 0.774 vs 0.759; p < 0.001). Comparisons were consistent across subgroups of age, infectious diagnoses, and comorbidities.ConclusionsThe Adult Sepsis Event's eSOFA organ dysfunction criteria identify a smaller, more severely ill sepsis cohort compared with the Sequential Organ Failure Assessment score, but with good overlap and similar clinical characteristics. Adult Sepsis Events may facilitate wide-scale automated sepsis surveillance that tracks closely with the more complex Sepsis-3 criteria.

Dataset Information

A novel C5a-neutralizing mirror-image (l-)aptamer prevents organ failure and improves survival in experimental sepsis.

Publications

A novel C5a-neutralizing mirror-image (l-)aptamer prevents organ failure and improves survival in experimental sepsis.

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