Examinando por Autor "Ayuso, Irene"

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TLR4-Binding DNA aptamers show a protective effect against acute stroke in animal models
(2018-08-01) Fernández, Gerónimo; Moraga, Ana; Cuartero, María; García-Culebras, Alicia; Peña-Martínez, Carolina; Pradillo, Jesús; Hernández-Jiménez, Macarena; Sacristán, Silvia; Ayuso, Irene; Gonzalo-Gobernado, Rafael; Fernández López, David; Martín, Elena; Moro, María; González, Víctor; Lizasoain, Ignacio
Since Toll-like receptor 4 (TLR4) mediates brain damage after stroke, development of TLR4 antagonists is a promising therapeutic strategy for this disease. Our aim was to generate TLR4-blocking DNA aptamers to be used for stroke treatment. From a random oligonucleotide pool, we identified two aptamers (ApTLR#1R, ApTLR#4F) with high affinity for human TLR4 by systematic evolution of ligands by exponential enrichment (SELEX). Optimized truncated forms (ApTLR#1RT, ApTLR#4FT) were obtained. Our data demonstrate specific binding of both aptamers to human TLR4 as well as a TLR4 antagonistic effect. ApTLR#4F and ApTLR#4FT showed a long-lasting protective effect against brain injury induced by middle cerebral artery occlusion (MCAO), an effect that was absent in TLR4-deficient mice. Similar effects were obtained in other MCAO models, including in rat. Additionally, efficacy of ApTLR#4FT in a model of brain ischemia-reperfusion in rat supports the use of this aptamer in patients undergoing artery recanalization induced by pharmacological or mechanical interventions. The absence of major toxicology aspects and the good safety profile of the aptamers further encourage their future clinical positioning for stroke therapy and possibly other diseases in which TLR4 plays a deleterious role.