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Terapia génica de supresión y reemplazo de KCNQ1 para el síndrome de QT largo tipo 1

Steven M Dotzler¹, C S John Kim¹, William A C Gendron²

¹Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (S.M.D., C.S.J.K., W.Z., D.Y., J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN.

|January 28, 2021

Resumen

Este estudio presenta una nueva terapia génica para el síndrome de QT largo (LQT1) que suprime y reemplaza el gen KCNQ1 defectuoso. Este enfoque corrigió con éxito la repolarización cardíaca en células derivadas del paciente, ofreciendo un tratamiento molecular potencial para LQT1.

Área de la Ciencia:

Genética cardiovascular
Terapia molecular
Tecnologías de edición de genes

Sus antecedentes:

El síndrome de QT largo tipo 1 (LQT1) surge de variantes de pérdida de función en el gen KCNQ1, crucial para la repolarización cardíaca.
Los tratamientos actuales para LQT1 no abordan la causa molecular subyacente de la afección.

Objetivo del estudio:

Desarrollar y evaluar una nueva terapia génica de doble componente (KCNQ1-SupRep) para corregir el LQT1.
Evaluar la eficacia de KCNQ1- SupRep en la supresión de las variantes de KCNQ1 que causan enfermedades y en el restablecimiento de la función genética normal.

Principales métodos:

Una sola construcción, KCNQ1-SupRep, fue diseñada para suprimir simultáneamente el KCNQ1 mutante y reemplazarlo con un cDNA KCNQ1 funcional y corto resistente al ARN de la horquilla.
Se realizaron experimentos con células TSA201 y cardiomiocitos derivados de células madre pluripotentes inducidas en humanos (iPSC-CM) de pacientes con LQT1.
La duración del potencial de acción (APD) se midió utilizando el tinte de tensión FluoVolt en iPSC-CM tratados con KCNQ1- SupRep.

Principales resultados:

KCNQ1- SupRep demostró supresión y reemplazo independientes de la mutación de las variantes de KCNQ1 en las células TSA201.
En los iPSC-CM derivados de pacientes de LQT1, el tratamiento con KCNQ1- SupRep acortó significativamente la duración prolongada del potencial de acción cardíaca (APD).
Los valores de APD en los iPSC-CM tratados se normalizan a niveles comparables con los controles isogénicos.

Conclusiones:

Este estudio proporciona la primera prueba de principio para una terapia génica capaz de corregir por completo el síndrome del intervalo QT largo.
La terapia génica KCNQ1-SupRep suprime y reemplaza efectivamente el gen KCNQ1, normalizando la repolarización cardíaca.
Los hallazgos sugieren que KCNQ1- SupRep es una estrategia terapéutica prometedora para LQT1 al eliminar su característica APD prolongada.

Palabras clave:

Proteína KCNQ1, humana Terapia genética células madre pluripotentes inducidas síndrome del intervalo QT largo

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