Temporal biomarker-powered immunotherapy targeting gfap for traumatic brain injury
Ended Project Grant Awarded Last action
- Award ID
- R44NS117221
- Recipient
-
Gryphon Bio Inc. UEI GNX8BTRL8915
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,497,195
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date
- Originally
- Funding
-
- $998,130.00 Federal
- $499,065.00 Non-federal
- Place of performance
- South San Francisco, CA 94080, USA
Award details come from USAspending.gov.
Description
- Abstract
- Traumatic brain injury (TBI) is a leading cause of mortality and morbidity in the US, with over two million new patients each year and no FDA-approved therapeutics. TBI induces an early, high concentration wave of cytotoxic glutamate into synapses that exceeds the buffering capacity of astroglial glutamate transporters (e.g. GLT-1), causing injury and death of brain cells. Under these neurotrauma conditions, the calpain- generated, 38 KDA core breakdown product of glial fibrillary acidic protein (gbdp) was released from injured astrocytes within hours to days post-injury. In parallel, other protein "debris" are released from neuronal cell bodies (ubiquitin c terminal hydrolase 1 /UCH-L1) and injured axons (neurofilament-heavy /PNF-h and light /NF-l, TAU and phosphorylated TAU /p-TAU). In fact, our most recent clinical data from track-TBI and center-TBI multicenter consortium studies showed that gfap/gdbps are the most the abundant protein debris released into the circulation after TBI. Significantly, we and others discovered that gbdps are prone to form protein aggregates that are neurotoxic when externalized. Grus and coworkers reported that anti-gfap antibodies have neuroprotective effects on cultured neuro-retinal cells and on retinal ganglion cells in organotypic culture under stress. Similarly, gbdp active immunization was neuroprotective in a mouse model of TBI, including attenuation of gbdp levels, reduction of key neuropathological biomarkers of TBI, and improvement of neurofunctional outcomes. Therefore, our central hypothesis is that passive immunotherapy with effector-competent IGG monoclonal antibodies (mabs) against gbdp will accelerate brain repair and improve cognition and other outcome measures in TBI patients. Our proposed mechanism of action is the beneficial opsonization of neurotoxic gbdp debris by anti-gbdp MAB (IGG), followed by accelerated phagocytosis by activated FCR+ phagocytes. Our content of use is TBI patients with a significant injury, as defined by moderate to severe TBI patients with initial GCS of 6-12 and elevated levels of selected acute temporal predictive biomarkers for targeted enrollment. Our proposed route of administration is intravenous multiday infusion of anti-gbdp mabs to maximize brain exposure, with subacute temporal pharmacodynamic (PD) biomarkers (such as gbdp, NFL, TAU and p-TAU) to track treatment response and adjust dosing. In this project, we leverage our synergistic expertise to test our hypothesis with (phase i) proof-of-concept in vitro and cell-based studies prior to (phase II) in vivo dose-ranging and efficacy studies to prioritize and characterize our lead anti-gbdp MAB immunotherapy candidates. Our preliminary preclinical studies now show that pre-injury, active immunization with gdbp and post- injury passive immunotherapy with anti-gbdp mabs are safe and beneficial in TBI mice. Moreover, we show how PD biomarkers might be employed to track treatment response and adjust dosing for successful translation from the laboratory to the clinic and to aid in meaningful benefit-risk decision-making.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $499,065 | $0 | |
| Original award | $499,065 | $499,065 |
Quick answers
Who received award R44NS117221?
R44NS117221 was awarded to Gryphon Bio Inc. by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on September 15, 2021.
How much is award R44NS117221 worth?
$1,497,195 has been obligated on R44NS117221: $998,130 in federal funding and $499,065 in non-federal funding.
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