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Un marco para la terapia individualizada con oligonucleótidos de conmutación de empalme

Jinkuk Kim^1,2,3,4, Sijae Woo⁵, Claudio M de Gusmao^6,7

¹Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. jinkuk@kaist.ac.kr.

|July 12, 2023

Resumen

La secuenciación de todo el genoma identificó a individuos con enfermedades genéticas, como la ataxia-telangiectasia, susceptibles a los oligonucleótidos antisentido de conmutación de empalme (ASO). Estos ASO corrigieron con éxito los defectos de empalme en las células de los pacientes y mostraron seguridad en un ensayo clínico.

Área de la Ciencia:

La genética
Biología molecular
Medicamentos para la salud

Sus antecedentes:

Las enfermedades genéticas plantean desafíos para las terapias dirigidas.
La identificación de individuos adecuados para la terapia de conmutación de empalme con oligonucleótidos antisenso (ASO) requiere un análisis genético avanzado.
La ataxia-telangiectasia es un trastorno genético recesivo grave y potencialmente mortal.

Objetivo del estudio:

Identificar sistemáticamente a las personas con enfermedades genéticas, específicamente ataxia-telangiectasia, que son candidatas para la terapia de conmutación de empalme ASO.
Desarrollar y validar un modelo predictivo para la adaptabilidad de ASO.
Demostrar la eficacia y seguridad de los ASO en entornos preclínicos y clínicos.

Principales métodos:

Secuenciación de todo el genoma de 235 individuos con ataxia-telangiectasia.
Desarrollo de una taxonomía predictiva para la capacidad de modulación de empalme de ASO.
Diseño y ensayo de ASO con conmutación de empalme en fibroblastos derivados de pacientes.
Estudio clínico piloto de un ASO en un paciente pediátrico.

Principales resultados:

Logrado un diagnóstico molecular casi completo para todos los participantes.
Se identificaron el 9% y el 6% de individuos con variantes "probablemente" o "posiblemente" susceptibles al tratamiento con ASO, respectivamente.
Desarrolló ASOs que corrigieron defectos de empalme y restauraron la señalización ATM en las células del paciente.
Se ha demostrado una buena tolerabilidad y seguridad de un ASO en un estudio clínico piloto de tres años.

Conclusiones:

La secuenciación de todo el genoma combinada con el modelado predictivo puede identificar pacientes para la terapia ASO.
Las variantes intrónicas profundas, a menudo pasadas por alto por otros métodos, pueden ser objeto de ASOs.
Este estudio proporciona un marco para la identificación prospectiva de pacientes que se benefician de tratamientos basados en ASO para trastornos genéticos.

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