tPA and NGF therapy for stroke - Principal Investigator/Program Director (Last, First, Middle: Soon Seog Jeong
Abstract
Due to its narrow time-window of administration (up to 4.5 hours post symptoms) and 6-7 fold increased risk
of intracranial hemorrhage, merely 3-5% of acute ischemic stroke patients receive recombinant tissue
plasminogen activator (tPA), the only FDA-approved drug for this indication. NGF prevents neuronal apoptosis
in primary cultured neurons and reduces neuronal degeneration in animal models of neurodegenerative
diseases. In the central nervous system, NGF is produced throughout adult life and primarily targets basal
forebrain and striatal neurons. It has been shown that intranasal (IN) NGF bypassed the blood-brain barrier and
distributed in the whole brain without peripheral adverse effects. IN administration of wildtype NGF significantly
reduced 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 stroke
onset.
We have optimized a human NGF variant and developed a cost-effective protein production system for
making the variant. This proprietary variant selectively activates the NGF TrkA receptor with enhanced activity
to promote neuron survival and function. In a randomized and blinded study in rats, IN treatment with the variant
for 3 weeks 6h after thrombo-embolic stroke (outside the therapeutic treatment time window for rt-PA) robustly
improved short- and long-term neurological deficit score as assessed 28 days after stroke. In this study, we will
follow the STAIR recommendations and RIGOR guidelines to conduct a Phase I preclinical study to validate the
the combination treatment with tPA in a rat model of stroke using both male and female animals. The long-term
goal is to develop the dug candidate as acute or sub-acute therapy, alone or in combination with tPA, to safely
reduce disability for millions of stroke patients.
Specific Aim. Determine whether combining tPA with the proprietary NGF variant more effectively improves
long-term outcomes compared to vehicle and tPA in a rat model of thrombo-embolic stroke when administered
at 6h after occlusion.
