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Analysis of circulating microRNAs as biomarkers predictive of haemorrhagic transformation in cerebral ischaemia after rt-PA administration. Clinical and preclinical study.
Stroke is a sudden disturbance of cerebral blood flow that temporarily or permanently alters the function of a specific region of the brain. Eighty-five percent of strokes are the result of arterial occlusion (ischaemic stroke or cerebral infarction). Recombinant tissue plasminogen activator (rt-PA) is currently the only effective drug for the treatment of acute ischaemic stroke when administered within 4.5 hours of the onset of symptoms. However, the risk of haemorrhagic transformation (HT) of the ischaemic lesion associated with the administration of rt-PA, which can contribute to neurological deterioration in patients, is an important limitation to the widespread use of rt-PA, which currently accounts for only 5-7% of patients with ischaemic stroke. Approximately 8% of patients treated with rt-PA may suffer symptomatic HT, which is associated with neurological deterioration and significantly worsens the prognosis of patients. The exact mechanisms underlying the onset of this complication are unknown. Given that thrombolytic therapy with rt-PA is currently the only approved pharmacological treatment for cerebral ischemia, research on biomarkers that predict HT associated with its administration is crucial to improve the risk/benefit of administering this drug and even to consider wider administration routes, increasing the percentage of patients who may benefit.
The identification of a profile of circulating miRNAs that predict the risk of HT before receiving treatment with rt-PA will make it possible to predict the onset of this complication and will help to better select patients who are candidates for the administration of this drug and to reduce the risk of HT in patients with ischaemic stroke. At the same time, the availability of these biomarkers may also allow the current therapeutic range of 4.5 hours from the onset of symptoms to be extended, thus increasing the percentage of patients who can benefit from the only drug approved to date for the treatment of acute ischaemic stroke.
On the other hand, the functional studies of miRNAs identified with the in vitro BBB model allow us to increase our knowledge of the pathophysiological mechanisms related to the appearance of HT, which may lead to the identification of new therapeutic targets for acute ischaemic stroke.
The objectives of the project are:
- To identify circulating microRNAs (miRNAs) in blood samples obtained at the time of admission of patients with ischaemic stroke, prior to the administration of rt-PA, that can predict the risk of HT of the ischaemic lesion after treatment with this thrombolytic drug.
- To evaluate in a cellular model (in vitro) whether the circulating miRNAs identified have a functional implication in this complication associated with treatment with rt-PA in order to increase knowledge of the mechanisms underlying HT.