Descripción del proyecto
Terapias moleculares dirigidas contra la esclerosis lateral amiotrófica
Los pacientes que padecen esclerosis lateral amiotrófica (ELA) experimentan una neurodegeneración progresiva. Aunque su etiología genética precisa sigue sin conocerse, una expansión hexanucleótida en uno de los intrones del gen C9ORF72 es la mutación genética relacionada con mayor frecuencia con la enfermedad. Los científicos del proyecto Combat_ALS, financiado con fondos europeos, trabajan en el desarrollo de herramientas terapéuticas para contrarrestar los efectos dañinos causados por los ARN que contienen repeticiones como resultado de la transcripción del C9ORF72. Se probarán distintos agentes químicos, incluidos oligonucleótidos antisentido, y se evaluará su eficacia en modelos celulares y organoides cerebrales humanos.
Objetivo
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that occurs in families, and sporadically in individuals. It was recently discovered that the massive expansion of a GC-rich hexanucleotide in the intron of the gen C9orf72 is its most frequent genetic cause. Many efforts have been dedicated to decipher the mechanisms by which this repeat expansion contributes to the disease. Although not completely understood, the most prominent mechanism suggested is the toxicity mediated by bidirectional transcription of RNA containing expansion of the repeated motif. These transcripts form nuclear RNA foci may sequester RNA-binding proteins (RBPs) leading to a loss of function. Recent investigations have reported on RBPs that specifically interact with quadruplex structures formed by repeat-containing C9orf72 RNAs. All these evidences make C9orf72 a very promising therapeutic target for ALS.
This proposal is focused on the development of new therapeutic tools based on targeting C9orf72 repeat-containing RNA. The objective is finding chemical agents able to counteract the toxicity induced by these RNAs. I will explore antisense and siRNA oligonucleotides containing novel chemical modifications with improved properties. I will study their structure, stability and silencing potencies. Moreover, I propose to use new screening methods to find small compounds with good affinity and specificity for C9orf72 repeats. This proposal includes an in-depth study of the binding mode of the most promising ligands by high resolution NMR, and in vivo testing. For this final aim, I will address the generation of human cerebral organoids carrying C9orf72 repeat expansion and their use to test the therapeutic strategies mentioned above.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-GF - Global FellowshipsCoordinador
28006 Madrid
España