Principal Investigator/Program Director (Last, First, Middle: Soon Seog Jeong Due to its narrow time-window of administration (up to 4.5 hours post symptoms) and 6-7 fold increased riskof intracranial hemorrhage, merely 3-5% of acute ischemic stroke patients receive recombinant tissueplasminogen activator (tPA), the only FDA-approved drug for this indication. NGF prevents neuronal apoptosisin primary cultured neurons and reduces neuronal degeneration in animal models of neurodegenerativediseases. In the central nervous system, NGF is produced throughout adult life and primarily targets basalforebrain and striatal neurons. It has been shown that intranasal (IN) NGF bypassed the blood-brain barrier anddistributed in the whole brain without peripheral adverse effects. IN administration of wildtype NGF significantlyreduced infarct volume and improved neurological outcomes by protecting neurons from ischemic injury,promoting angiogenesis, and enhancing striatal neurogenesis with at least a 24h treatment window after strokeonset. We have optimized a human NGF variant and developed a cost-effective protein production system formaking the variant. This proprietary variant selectively activates the NGF TrkA receptor with enhanced activityto promote neuron survival and function. In a randomized and blinded study in rats, IN treatment with the variantfor 3 weeks 6h after thrombo-embolic stroke (outside the therapeutic treatment time window for rt-PA) robustlyimproved short- and long-term neurological deficit score as assessed 28 days after stroke. In this study, we willfollow the STAIR recommendations and RIGOR guidelines to conduct a Phase I preclinical study to validate thethe combination treatment with tPA in a rat model of stroke using both male and female animals. The long-termgoal is to develop the dug candidate as acute or sub-acute therapy, alone or in combination with tPA, to safelyreduce disability for millions of stroke patients. Specific Aim. Determine whether combining tPA with the proprietary NGF variant more effectively improveslong-term outcomes compared to vehicle and tPA in a rat model of thrombo-embolic stroke when administeredat 6h after occlusion.
Public Health Relevance Statement: Principal Investigator/Program Director (Last, First, Middle: Soon Seog Jeong
Narrative
The proprietary NGF analog is a safe and powerful protector and inducer of neurons. We propose to
determine whether the combination treatment with FDA approved r-tPA will be safe and beneficial with at least
a 6h therapeutic treatment window after stroke in a clinically relevant model of thrombo-embolic stroke in adult
rats.
Project Terms: Intranasal Administration ; Intranasal Drug Administration ; Adult ; 21+ years old ; Adult Human ; adulthood ; Animals ; Blood - brain barrier anatomy ; Blood-Brain Barrier ; Hemato-Encephalic Barrier ; bloodbrain barrier ; Brain ; Brain Nervous System ; Encephalon ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Cells ; Cell Body ; Clinical Trials ; Clone Cells ; comorbidity ; co-morbid ; co-morbidity ; Complication ; Corpus striatum structure ; Corpus Striatum ; Striate Body ; Striatum ; striatal ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Edema ; Dropsy ; Hydrops ; Enzymes ; Enzyme Gene ; Escherichia coli ; E coli ; E. coli ; Exhibits ; Eyedrops ; Eye Drops ; Female ; Glaucoma ; glaucomatous ; Goals ; Growth ; Generalized Growth ; Tissue Growth ; ontogeny ; Disabled Persons ; Disabled Population ; Handicapped ; People with Disabilities ; Persons with Disabilities ; disabled ; disabled individual ; disabled people ; individuals with disabilities ; Human ; Modern Man ; Infarction ; infarct ; male ; Mus ; Mice ; Mice Mammals ; Murine ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; Nerve Growth Factors ; Neuronotrophic Factors ; Neurotrophic Proteins ; Nervous System Physiology ; Neurologic function ; Neurological function ; nervous system function ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Patients ; Alteplase ; Recombinant Tissue Plasminogen Activator ; T-Plasminogen Activator ; Tissue Activator D-44 ; Tissue Plasminogen Activator ; Tissue-Type Plasminogen Activator ; t-PA ; Production ; Proteins ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Recommendation ; Retinal Ganglion Cells ; retinal ganglion ; Risk ; Safety ; Peptide Signal Sequences ; Signal Peptide ; Signal Sequences ; protein signal sequence ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Stroke ; Apoplexy ; Brain Vascular Accident ; Cerebral Stroke ; Cerebrovascular Apoplexy ; Cerebrovascular Stroke ; brain attack ; cerebral vascular accident ; cerebrovascular accident ; Suspensions ; Suspension substance ; Technology ; Time ; Trypsin ; Tripcellim ; Work ; Neurotrophic Tyrosine Kinase Receptor Type 1 ; NTRK1 Receptor ; Nerve Growth Factor Receptor Type 1 ; p140-trkA ; trk1 Transforming Tryrosine Kinase ; trkA Receptor ; Mediating ; promoter ; promotor ; Blinded ; Intracranial Hemorrhages ; Cell Density ; Apoptosis ; Apoptosis Pathway ; Programmed Cell Death ; Investigational New Drug Application ; Guidelines ; Injury ; injuries ; improved ; Peripheral ; Acute ; Clinical ; Phase ; Variant ; Variation ; Chemicals ; Serum ; Blood Serum ; disability ; Memory impairment ; Memory Deficit ; memory dysfunction ; Recovery ; analog ; AQP4 protein ; aquaporin 4 ; Therapeutic ; angiogenesis ; Attenuated ; cleaved ; Cleaved cell ; Life ; programs ; Hour ; System ; brain tissue ; Neurologic Deficit ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; mutant ; expression vector ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; Bypass ; neurogenesis ; Modeling ; stroke treatment ; treating stroke ; stroke therapy ; Brain Trauma ; traumatic brain damage ; Traumatic Brain Injury ; Adverse effects ; CNS Nervous System ; Central Nervous System ; Neuraxis ; Ischemic Stroke ; Molecular Interaction ; Binding ; preventing ; prevent ; Address ; Symptoms ; Data ; randomisation ; randomization ; randomly assigned ; Randomized ; Receptor Signaling ; Validation ; Principal Investigator ; Process ; Modification ; neuron apoptosis ; apoptosis of neuronal cells ; neuronal apoptosis ; neuronal cells programmed cell death ; neurons programmed cell death ; programmed cell death of neuronal cells by apoptosis ; programmed cell death of neurons by apoptosis ; pre-clinical ; preclinical ; preclinical study ; pre-clinical study ; post stroke ; after stroke ; poststroke ; stroke recovery ; basal forebrain ; Biodistribution ; Outcome ; post stroke depression ; poststroke depression ; cost effective ; Neurological outcome ; Neurologic outcome ; aged ; Synaptic plasticity ; innovation ; innovate ; innovative ; clinically relevant ; clinical relevance ; Alzheimer's disease model ; AD model ; alzheimer model ; FDA approved ; neurovascular ; neuro-vascular ; preservation ; stroke patient ; stroke model ; stroke outcome ; thromboembolic stroke ; ischemic injury ; ischemia injury ;
