# A novel thrombolytic targeting Von Willebrand Factor (VWF) to treat ischemic stroke

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $564,013

## Abstract

PROJECT SUMMARY
Arterial thrombosis resulting in acute ischemic stroke (AIS) is the leading cause of combined morbidity and
mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only drug approved to treat AIS.
Unfortunately, only ~5-10% of patients who present with AIS actually receive rtPA. Risks of rtPA treatment
include a significant increase in symptomatic intracranial hemorrhage (ICH), which occurs in up to 6.4% of
patients who receive the drug. Moreover, rtPA only achieves 10% recanalization in patients who present with
large vessel occlusion (LVO) stroke. These clots, which are commonly platelet-rich, are notoriously resistant to
rtPA. A critical need exists to develop thrombolytic agents that: 1. target critical proteins involved in
stroke clot architecture, 2. recanalize arterial occlusions, and 3. have a safety profile superior to rtPA.
Von Willebrand Factor (VWF) is an optimal target for AIS treatment. VWF binds to glycoprotein Ib (GPIb) of
the platelet receptor complex GPIb-IX-V as well as to GPIIb-IIIa, resulting in platelet activation and aggregation.
VWF also self-associates, extending into the vessel lumen as a scaffold for platelet and red blood cell adhesion.
These processes result in arterial thrombosis as seen in AIS patients. Our preliminary data of cerebral thrombi
from stroke patients show that the majority of clots have a platelet shell rich with VWF encapsulating the
thrombus core, providing an explanation for the poor arterial recanalization rate associated with rtPA.
Aptamers are oligonucleotide-based drugs that inhibit their target proteins with high affinity and specificity. We
have isolated and optimized an RNA aptamer that binds to and inhibits VWF (DTRI-031). We have also
designed a second oligonucleotide (DTRI-025) that fully reverses DTRI-031 activity within minutes. Our
data in small and large animal models of thrombosis demonstrates that DTRI-031 both prevents thrombus
formation and lyses fully formed arterial occlusions better than rtPA. The overall goals of this proposal are to 1)
correlate elevated plasma VWF to clot VWF in AIS patients and 2) demonstrate VWF inhibition by DTRI-031 can
translate into an effective treatment for patients who present with AIS.
We will test the hypotheses that 1) VWF is an optimal target for AIS treatment. Our preliminary data shows
that LVO AIS patients have significantly elevated plasma VWF. Our preliminary data has replicated these
findings in a murine model of stroke. 2) DTRI-031 effectively lyses clots in vitro in blood samples from AIS
patients and in vivo in a murine model of stroke. Moreover, DTRI-025 rapidly reverses DTRI-031 activity in AIS
in vitro and in vivo. 3) DTRI-031 treatment improves outcomes in a murine model of AIS by increasing
recanalization, decreasing infarct volume, and improving functional recovery. Our preliminary data reveals that
DTRI-031-treated mice have reduced post-stroke infarct volumes compared to control. Finally, DTR...

## Key facts

- **NIH application ID:** 10289825
- **Project number:** 1R01NS123687-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Shahid Nimjee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $564,013
- **Award type:** 1
- **Project period:** 2021-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10289825

## Citation

> US National Institutes of Health, RePORTER application 10289825, A novel thrombolytic targeting Von Willebrand Factor (VWF) to treat ischemic stroke (1R01NS123687-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10289825. Licensed CC0.

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