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Principal Investigator: Martin Stengelin
Organization: MESO SCALE DIAGNOSTICS, LLC
Fiscal Year: 2024
Award: $435,526
Funding agency: National Institute of Neurological Disorders and Stroke
This industrial-academic collaboration seeks to analytically validate a highly specific and sensitive
multiplexed immunoassay for glial fibrillary acid protein (GFAP) and tau in serum and/or plasma to improve
treatment decisions for neonates with hypoxic-ischemic encephalopathy (HIE). HIE, which affects
approximately 1 in every 1,000 births, is a major cause of death and disability for children. Prompt whole body
cooling of neonates improves outcomes in some cases; however, 24% of cooled neonates die from HIE, and
19% of survivors develop cerebral palsy despite best available treatment. Adjuvants to hypothermia promise
to broaden the effectiveness of treatment. Clinical testing of these investigational adjuvants has been slow due
to the difficulty in identifying neonates who are most likely to benefit from treatment. By prescreening neonates
at the extremes of the injury spectrum, an objective simple blood test that stratifies neonates according to
injury severity and monitors treatment responses would accelerate trials of investigational adjuvants.
The multiplex employs a novel format with approximately 100-1,000x higher sensitivity than regular
immunoassays, which improves quantitation in the clinically relevant ranges of these low abundance
biomarkers. Our preliminary data demonstrate that our new assay format is sufficiently sensitive to measure
GFAP and tau in serum and plasma. Collaborators at Johns Hopkins University (Drs. Everett and Northington)
have demonstrated clinical utility of GFAP and tau as markers of injury severity and functional outcomes in
HIE. This proposal seeks to fully develop and optimize the ultrasensitive multiplex using our phase-gated
process, followed by extensive analytical validation.
First-year tasks are extensive characterization of key critical reagents, assay fine-tuning, and establishment
of analytical controls at key concentrations for stratifying neonates according to HIE severity. A risk analysis
will be performed, and the effect of preanalytical factors and potential interferents will be assessed and
mitigated. In year two, the design will be frozen and transferred to manufacturing. QC protocols for critical
reagents will be established and executed, and components will be configured following MSD’s ISO
9001:2015-certified quality management system. Three kit lots at final design will be manufactured. Assay
performance will be assessed throughout the project, and include testing of clinical samples. A formal
analytical assay validation plan will be developed in collaboration with a clinical chemist (Dr. Sokoll from JHU),
with input from the NIH Program Officers, and based on the 2018 FDA Bioanalytical Method Validation
Guidance for Industry. The final analytical validation study will be performed at three sites: MSD, Johns
Hopkins Hospital, and All Children’s Hospital. Multi-site testing will include testing of proficiency samples, a
20-day reproducibility study, and a lot-to lot comparison. Additionally, real-time and accelerated stability tests
will be performed in year 4.
Terms: <0-11 years old><ANOVA><Acceleration><Acquired brain injury><Adjuvant><Adjuvant Study><Adjuvant Trials><Affect><Analysis of Variance><Animal Model><Animal Models and Related Studies><Asphyxia><Assay><Astroprotein><Bioassay><Biological Assay><Biological Markers><Biometrics><Biometry><Biostatistics><Birth><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Serum><Blood Tests><Body System><Brain Injuries><Caring><Cause of Death><Cerebral Palsy><Certification><Cessation of life><Child><Child Youth><Children (0-21)><Children's Hospital><Clinical><Clinical Chemistry><Clinical Evaluation><Clinical Testing><Clinical Treatment><Clinical Trials><Clinical Trials Design><Collaborations><Data><Death><Development><Diagnostic><ELISA><Effectiveness><Ensure><Enzyme-Linked Immunosorbent Assay><Evaluation><Freezing><Funding><GFA-Protein><GFAP><Glial Fibrillary Acid Protein><Glial Fibrillary Acidic Protein><Glial Intermediate Filament Protein><Goals><Guidelines><Hematologic Tests><Hematological Tests><Hematology Testing><Heterogeneity><Hospitals><Hour><Hypothermia><Immunoassay><Individual><Industrialization><Industry><Injury><Laboratories><Life><Lifelong disability><MR Imaging><MR Tomography><MRI><MRIs><MT-bound tau><Magnetic Resonance Imaging><Measurement><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medicine><Methods><Monitor><Multi-Institutional Clinical Trial><Multi-center clinical trial><Multi-site clinical trial><Multicenter clinical trial><Multisite clinical trial><NIH><NMR Imaging><NMR Tomography><National Institutes of Health><Neonatal Intensive Care Units><Nervous System Injuries><Nervous System Trauma><Nervous System damage><Neurologic outcome><Neurological Damage><Neurological Injury><Neurological outcome><Neurological trauma><Newborn Intensive Care Units><Nuclear Magnetic Resonance Imaging><Organ System><Outcome><Participant><Parturition><Pediatric Hospitals><Performance><Perinatal><Peripartum><Permanent disability><Phase><Plasma><Plasma Serum><Predisposition><Process><Prognosis><Prospective Studies><Protocol><Protocols documentation><Qualifying><Reagent><Recovery><Reporting><Reproducibility><Research><Reticuloendothelial System, Serum, Plasma><Risk><Running><Sampling><Serum><Severities><Site><Suffocation><Survivors><Susceptibility><System><Target Populations><Testing><Therapeutic><Time><Treatment Effectiveness><United States National Institutes of Health><Universities><Validation><Variance Analyses><Zeugmatography><adjuvant protocol><asphyxiation><bio-markers><biologic marker><biomarker><brain damage><brain-injured><clinical relevance><clinical test><clinically relevant><cross reactivity><customized therapy><customized treatment><data deposition><data submission><design><designing><developmental><disability><enzyme linked immunoassay><functional outcomes><hypoxic ischemic encephalopathy><improved><improved outcome><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><injuries><innovate><innovation><innovative><instrument><kids><manufacturability><manufacture><microtubule bound tau><microtubule-bound tau><model of animal><multiplex assay><natural hypothermia><neonatal HIE><neonatal ICU><neonatal hypoxia-ischemia><neonatal hypoxic-ischemic brain injury><neonatal hypoxic-ischemic encephalopathy><neonate><neural imaging><neuro-imaging><neuroimaging><neurological imaging><neurotrauma><novel><outcome prediction><patient specific therapies><patient specific treatment><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><predict responsiveness><predicting response><programs><research clinical testing><response to therapy><response to treatment><screening><screenings><stability testing><tailored medical treatment><tailored therapy><tailored treatment><tau><tau Proteins><tau factor><therapeutic response><therapy response><tool><treatment response><treatment responsiveness><trial regimen><trial treatment><unique treatment><validation studies><validations><youngster><τ Proteins>