Document text
Principal Investigator: Alan Koretsky
Organization: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Fiscal Year: 2023
Award: $1,080,628
Funding agency: National Institute of Neurological Disorders and Stroke
We have made substantial progress towards Aims 1-5, 7&8. Specifically:
a) We have demonstrated that a mutant mouse transferrin receptor binding nanobody with strong pH dependent unbinding crosses the BBB in vivo approximately 500 times more effectively than a control nanobody.
b) We have demonstrated that the mutant mouse transferrin receptor binding nanobody can carry other nanobodies as cargo across the mouse BBB. A tandem dimer of nanobodies that bind to the P2X7 receptor has been used as a model cargo.
c) We have shown that cargo transported across the BBB can be detected in capillary depleted brain lysates and histochemically at their target sites between 1 and 16 hours after injection.
d) We have demonstrated that there is a strong nonlinearity in the dose-response curve for the BBB crossing nanobodies. At doses greater than 30 nmol/kg injected intravenously, there is no greater brain accumulation of cargo. The maximum brain concentration achieved was 4.5 nM. This concentration is an order of magnitude too low for MRI detection of iron oxide nanoparticles. We therefore have decided to switch to PET imaging for further development molecular contrast imaging agents.
e) We are developing methods to conjugate nanobodies to the positron emitting Copper-64 for PET scans.
f) We have established a new collaboration with Dr. Dale Kiesewetter and his research group to perform PET scans in living mice at multiple time points after injection.
g) We have initiated new collaborations with M Janoswki at U Maryland, D Sehlin and S. Syvanen at Uppsala U, and I Huggins at Ionis Pharmaceuticals to perform additional imaging studies using our BBB crossing nanobody constructs.
h) We have established new collaborations with Dr F. Nugent at USUHS, Dr. N. Plesnila at U Munich, and Dr. F. Porreca at U Arizona to test our nanobody constructs for efficacy as BBB crossing P2X7 receptor blocking therapeutics in mouse models of TBI, stroke, and post-traumatic headache.
i) Ongoing work by our collaborators at Washington University indicates that our SARS-CoV-2 nanobodies have potential for use in real time environmental surveillance of aerosols and for detection of SARS-CoV-2 in exhaled breath.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acceleration><Aerosols><Apoplexy><Arizona><Assay><BBB crossing><Binding><Bioassay><Biologic Assays><Biological Assay><Blood - brain barrier anatomy><Blood capillaries><Blood-Brain Barrier><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><Brain Vascular Accident><CD71><COVID-19 detection><COVID-19 therapeutics><COVID-19 virus><COVID19 detection><COVID19 therapeutics><COVID19 virus><Cell Communication and Signaling><Cell Signaling><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><CoV-2><CoV2><Collaborations><Contrast Agent><Contrast Drugs><Contrast Media><Copper><Cu element><Detection><Development><Diagnosis><Diagnostic><Dose><Encephalon><Encephalon Diseases><Exhalation><Exhaling><Family><General Radiology><Goals><Health Sciences><Hemato-Encephalic Barrier><Hour><Human><Image><In Vitro><Individual><Injections><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Intravenous><Investigation><Investigators><Joints><Kinetics><Laboratories><Lead><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Maryland><Math Models><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Murine><Mus><Mutant Strains Mice><NIH><NINDS><NMR Imaging><NMR Tomography><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><National Institutes of Health><Nervous System Diseases><Neurologic><Neurologic Disorders><Neurological><Neurological Disorders><Neurosciences><Nuclear Magnetic Resonance Imaging><PET><PET Scan><PET imaging><PETSCAN><PETT><Pathologic><Patients><Pb element><Pharmaceutical Agent><Pharmaceuticals><Pharmacodynamics><Pharmacologic Substance><Pharmacological Substance><Positron><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Post-Traumatic Headaches><Posttraumatic Headaches><R-Series Research Projects><R01 Mechanism><R01 Program><Rad.-PET><Radiation exposure><Radiology><Radiology Specialty><Radiopaque Media><Receptor Protein><Regenerative Medicine><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Resolution><Respiratory Expiration><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 detection><SARS-CoV-2 therapeutics><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 therapeutics><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 therapeutics><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Site><Stroke><Supervision><TFR gene><TFR protein><TFR1><TFRC><TFRC gene><TRFR><Testing><Therapeutic><Time><Transferrin Receptor><Transferrin Receptor 1><Transgenic Mice><United States National Institutes of Health><Universities><University Health Services><Visualization><Washington><Work><Wuhan coronavirus><Zeugmatography><biological signal transduction><blood-brain barrier crossing><bloodbrain barrier><bloodbrain barrier crossing><brain MR imaging><brain MRI><brain attack><brain magnetic resonance imaging><capillary><cerebral MR imaging><cerebral MRI><cerebral magnetic resonance imaging><cerebral vascular accident><cerebrovascular accident><contrast imaging><coronavirus disease 2019 detection><coronavirus disease 2019 therapeutics><coronavirus disease 2019 virus><coronavirus disease-19 virus><cost><design><designing><detect COVID-19><detect COVID19><detect SARS-CoV-2><detect severe acute respiratory syndrome coronavirus 2><detection method><detection procedure><detection technique><developmental><dimer><drug discovery><hCoV19><heavy metal Pb><heavy metal lead><imaging><imaging agent><imaging study><improved><in vivo><intravenous injection><iron oxide nano particle><iron oxide nanoparticle><mathematic model><mathematical model><mathematical modeling><molecular modeling><molecular pathology><mouse model><mouse mutant><murine model><nCoV2><nanobodies><nanobody><nervous system disorder><neurological disease><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pharmaceutical><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><receptor><receptor binding><receptor bound><resolutions><response><sdAb><severe acute respiratory syndrome coronavirus 2 detection><single domain antibodies><stroked><strokes><therapeutic candidate><therapeutics against COVID-19><therapeutics against COVID19><therapeutics against SARS-CoV-2><therapeutics against SARS-coronavirus-2><therapeutics against Severe acute respiratory syndrome coronavirus 2><therapeutics against coronavirus disease 2019><therapeutics for novel coronavirus><transcytosis>