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Publication Number
US-11890471-B2
Publication Date
2024-02-06
Expiration Date
Abstract
Diagnostic screening tests that can be used to identify if a patient is a good candidates for an implantable vagus nerve stimulation device. One or more analyte, such as a cytokine or inflammatory molecule, can be measured from a blood sample taken prior to implantation of a vagus nerve stimulator to determine the patient's responsiveness to VNS for treatment of an inflammatory disorder.
Core Innovation
The disclosed invention provides in vitro and blood-based screening approaches to determine a patient’s responsiveness to vagus nerve stimulation (VNS) for treating an inflammatory disorder. In the in vitro approaches, blood samples are obtained from the patient prior to stimulation and are challenged with toxin, endotoxin, or LPS, and inflammatory cytokine release is measured to distinguish responders from non-responders for VNS.
For toxin-challenge screening, the method compares the amount of inflammatory cytokine released in response to a second toxin concentration versus a first toxin concentration. The patient is categorized as a responder or a non-responder based on the measured cytokine amounts released in response to the differing toxin concentrations, including determinations that use ratio comparisons and inflammatory response patterns across concentrations.
For stimulation-and-biomarker screening, the disclosed method measures a baseline level of C-reactive protein (CRP) in a patient blood sample, stimulates the vagus nerve, then measures a post-stimulation level of CRP in a blood sample taken after the stimulation. The method compares the post-stimulation CRP level to the baseline CRP level and indicates whether the patient is a suitable candidate for an implantable vagus nerve stimulation device based on that comparison.
Claims Coverage
The partial content includes three independent claims. Across these claims, the inventive features cover in vitro toxin challenge with inflammatory cytokine comparisons across at least two concentrations, in vitro LPS challenge with determination of an inflammatory response curve compared to a cutoff, and baseline-to-post stimulation CRP comparison to indicate suitability for an implantable VNS device.
In vitro cytokine comparison after toxin concentration step
Obtain a blood sample taken from the patient prior to stimulation, challenge the sample with a first concentration of toxin, obtain a second blood sample prior to stimulation, challenge the second sample with a second toxin concentration at least 2 times the first concentration, determine an amount of inflammatory cytokine released in response to the second concentration compared to the cytokine released in response to the first concentration, and output an indication that the patient is a responder or a non-responder for vagus nerve stimulation based on the amount of inflammatory cytokine released.
In vitro LPS response curve compared to cutoff for suitability
Obtain a blood sample taken from the patient prior to stimulation, challenge the sample with LPS at a first concentration, measure a level of an inflammatory cytokine released in response, challenge the sample with LPS at a second concentration at least 5 times the first concentration, measure the level of the inflammatory cytokine released in response, determine a response curve based on the cytokine levels, compare the response curve to a cutoff, and determine whether the patient is suitable for vagus nerve stimulation based on the comparison of the determined response curve to the cutoff.
Baseline-to-post stimulation CRP comparison for implantable device suitability
Measure a baseline level of CRP in a blood sample taken from the patient, stimulate the vagus nerve, measure a post-stimulation level of CRP in a blood sample taken after the vagus nerve has been stimulated, compare the post-stimulation CRP level to the baseline CRP level, and indicate if the patient is a suitable candidate for an implantable vagus nerve stimulation device based on the comparison.
Collectively, the independent claims provide screening decisions for VNS responsiveness using in vitro toxin-challenged inflammatory cytokine comparisons to classify responder versus non-responder, an in vitro LPS challenge that generates a response curve compared to a cutoff to decide suitability, and a stimulation-and-biomarker approach using baseline versus post-stimulation CRP to indicate suitability for an implantable VNS device.
Stated Advantages
Provides an indication whether a patient is a responder or a non-responder for vagus nerve stimulation based on inflammatory cytokine release.
Determines patient suitability for vagus nerve stimulation by comparing a determined response curve to a cutoff.
Indicates if the patient is a suitable candidate for an implantable vagus nerve stimulation device based on comparison of post-stimulation CRP to baseline CRP.
Documented Applications
Proof-of-concept with whole blood assay experiments in rheumatoid arthritis cohorts is described, including distinguishing nonresponders via endotoxin/toxin challenge and inflammatory cytokine response curve behavior.
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