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Modulación de la transcripción del ADN: ¿El futuro de las terapias ASO?

Anastasia Khvorova¹

¹RNA Therapeutic Institute, UMASS Chan Medical School, Worcester, MA 01581, USA.

|June 10, 2022

Resumen

Los investigadores encontraron que nusinersen, un medicamento para la atrofia muscular espinal (SMA), puede obstaculizar su propia eficacia al promover modificaciones represivas de la cromatina. La administración concomitante de inhibidores de la histona deacetilasa puede superar esta limitación, mejorando la inclusión de exones para un mejor tratamiento de la AME.

Área de la Ciencia:

Genética y Epigenética
Desarrollo de medicamentos terapéuticos
Enfermedades neurodegenerativas

Sus antecedentes:

La atrofia muscular espinal (AMS) es un trastorno genético grave que afecta a las neuronas motoras.
El tratamiento con oligonucleótidos antisenso (ASO), como el nusinersen, es un tratamiento clave para la AME.
Nusinersen actúa promoviendo la inclusión de exones en el gen SMN2.

Objetivo del estudio:

Investigar los posibles mecanismos que limitan la eficacia de nusinersen en el tratamiento de la AME.
Identificar estrategias para mejorar los beneficios terapéuticos del nusinersen.

Principales métodos:

Análisis de las modificaciones de la cromatina inducidas por el tratamiento con nusinersen.
Evaluación del impacto de las modificaciones represivas de la cromatina en la inclusión de exones.
Evaluación de la administración concomitante de inhibidores de la histona deacetilasa (HDAC) con nusinersen.

Principales resultados:

Se encontró que el tratamiento con Nusinersen induce modificaciones represivas de la cromatina.
Estas modificaciones se observaron para contrarrestar el efecto previsto de la inclusión de exones.
La administración concomitante de inhibidores de HDAC con nusinersen aumentó con éxito la inclusión de exones.

Conclusiones:

Las modificaciones represivas de la cromatina representan una limitación intrínseca del tratamiento con nusinersen para la AME.
Los inhibidores de la histona deacetilasa pueden superar esta limitación, ofreciendo una estrategia para mejorar la eficacia de la ASO.
Este hallazgo proporciona un nuevo enfoque para mejorar las terapias basadas en oligonucleótidos antisenso para la AME.

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