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DELIASE
Decarbamylation For Improved Lysis of Acute Ischemic Stroke Thrombi
FunderFrench National Research Agency (ANR)
Funder Contribution €412,410.00
DurationFrom 01 Apr 2024
Project codeANR-23-CE17-0023
Identifiers
Description
The management of the acute ischemic stroke (AIS) remains a major challenge for modern medicine. The main goal of AIS treatment is to recanalize the occluded artery by removing the thrombus causing the ischemia as quickly as possible. There are two treatment options: intravenous thrombolysis (IVT) and mechanical thrombectomy (MT), both of which have significant limitations. IVT aims at dissolving the thrombus by administering tissue plasminogen activator (t-PA), a drug that targets the thrombus fibrin network. However, IVT has a limited recanalization efficacy (75% success). Yet, MT requires access to highly specialized stroke centers, and is only indicated for patients with large artery strokes of the anterior circulation (20-30% of strokes) Therefore, there is still significant potential and a critical need for improvement of AIS recanalization therapy. Within the framework of the ANR axes C9 and C10 (translational research and Biomedical Innovation), we aim to study a new therapeutic strategy that would increase the efficacy of IVT, thus improving the outcome of a larger number patients. Our hypothesis, based on our preliminary data, is that carbamylation, a type of post-translational modification, occurs in AIS thrombi and limits the efficacy of IVT and MT. Our goal is therefore to demonstrate 1) that carbamylation of AIS thrombi negatively impacts their response to IVT and MT, and 2) that its reversal with a recombinant decarbamylase could provide the basis for the development of a new adjuvant treatment to improve recanalization therapy in AIS.
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The management of the acute ischemic stroke (AIS) remains a major challenge for modern medicine. The main goal of AIS treatment is to recanalize the occluded artery by removing the thrombus causing the ischemia as quickly as possible. There are two treatment options: intravenous thrombolysis (IVT) and mechanical thrombectomy (MT), both of which have significant limitations. IVT aims at dissolving the thrombus by administering tissue plasminogen activator (t-PA), a drug that targets the thrombus fibrin network. However, IVT has a limited recanalization efficacy (75% success). Yet, MT requires access to highly specialized stroke centers, and is only indicated for patients with large artery strokes of the anterior circulation (20-30% of strokes) Therefore, there is still significant potential and a critical need for improvement of AIS recanalization therapy. Within the framework of the ANR axes C9 and C10 (translational research and Biomedical Innovation), we aim to study a new therapeutic strategy that would increase the efficacy of IVT, thus improving the outcome of a larger number patients. Our hypothesis, based on our preliminary data, is that carbamylation, a type of post-translational modification, occurs in AIS thrombi and limits the efficacy of IVT and MT. Our goal is therefore to demonstrate 1) that carbamylation of AIS thrombi negatively impacts their response to IVT and MT, and 2) that its reversal with a recombinant decarbamylase could provide the basis for the development of a new adjuvant treatment to improve recanalization therapy in AIS.
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