Desarrollan un fármaco contra el Alzheimer sin secuelas inflamatorias

Desarrollan un fármaco contra el Alzheimer sin secuelas inflamatorias

Un equipo de investigadores del KAIST en Corea del Sur ha desarrollado un novedoso fármaco de proteína de fusión, aAB-Gas6, que elimina eficazmente el AB, importante en la enfermedad de Alzheimer, a través de un mecanismo totalmente diferente al de la inmunoterapia basada en anticuerpos AB.

En un modelo de ratón de la EA, aAB-Gas6 no sólo eliminó el AB con mayor potencia, sino que también evitó los efectos secundarios inflamatorios neurotóxicos asociados a los tratamientos convencionales con anticuerpos.

Aunque ‘Aduhelm’, un anticuerpo monoclonal dirigido a la beta amiloide (AB), se ha convertido recientemente en el primer fármaco aprobado en Estados Unidos frente a la enfermedad de Alzheimer (EA) por su capacidad para disminuir la carga de la placa AB en pacientes con EA, su efecto en la mejora cognitiva sigue siendo controvertido.

Además, alrededor del 40 por ciento de los pacientes tratados con este anticuerpo experimentaron efectos secundarios graves, como edemas cerebrales (ARIA-E) y hemorragias (ARIA-H) que probablemente están relacionados con las respuestas inflamatorias en el cerebro cuando el anticuerpo AB se une a los receptores Fc (FCR) de células inmunitarias como la microglía y los macrófagos.

Estos efectos secundarios inflamatorios pueden causar la muerte de células neuronales y la eliminación de sinapsis por parte de la microglía activada, e incluso tienen el potencial de exacerbar el deterioro cognitivo en los pacientes con EA. Así pues, la actual inmunoterapia basada en anticuerpos contra AB tiene el riesgo inherente de hacer más daño que bien debido a sus efectos secundarios inflamatorios.

“La activación del FcR por parte de los anticuerpos dirigidos a AB induce la fagocitosis de AB mediada por la microglía, pero también produce señales inflamatorias, dañando inevitablemente los tejidos cerebrales”, explican Chan Hyuk Kim y Won-Suk Chung, autores del estudio, que se ha publicado en la revista científica ‘Nature Medicine’.

El efecto antiinflamatorio de usar la eferocitosis

Por lo tanto, utilizaron la eferocitosis, un proceso celular por el que los fagocitos eliminan las células muertas como vía alternativa para la eliminación de AB en el cerebro. La eferocitosis va acompañada de respuestas antiinflamatorias para mantener la homeostasis de los tejidos.

“Para explotar este proceso, diseñamos Gas6, una proteína adaptadora soluble que media la eferocitosis a través de los receptores fagocíticos TAM de tal manera que su especificidad de destino se redirigió de las células muertas a las placas de AB”, detallan los responsables del trabajo.

Los profesores y su equipo demostraron que la aAB-Gas6 resultante inducía la engullición de AB activando no sólo la fagocitosis microglial, sino también la astrocítica, ya que los receptores fagocíticos TAM son altamente expresados por estos dos fagocitos principales en el cerebro.

Es importante destacar que aAB-Gas6 promovió la captación robusta de AB sin mostrar ningún signo de inflamación y neurotoxicidad, lo que contrasta fuertemente con el tratamiento utilizando un anticuerpo monoclonal AB.

Además, demostraron que el aAB-Gas6 reducía sustancialmente la eliminación excesiva de sinapsis por parte de la microglía, lo que conducía a una mejor recuperación del comportamiento en los ratones modelo de la EA.

“Utilizando un modelo de ratón de angiopatía amiloide cerebral (AAC), un trastorno cerebrovascular causado por el depósito de AB dentro de las paredes de los vasos sanguíneos del cerebro, también demostramos que la administración intratecal de la proteína de fusión Gas6 eliminaba significativamente los amiloides cerebrovasculares, junto con una reducción de las microhemorragias. Estos datos demuestran que el aAb-Gas6 es un potente agente terapéutico para eliminar el AB sin exacerbar las microhemorragias relacionadas con la AAC”, esgrimen.

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