Project description
Targeted molecular therapies against amyotrophic lateral sclerosis
Patients suffering from amyotrophic lateral sclerosis (ALS) experience progressive neurodegeneration. Although the precise genetic aetiology remains elusive, an hexanucleotide expansion in one of the introns of the C9ORF72 gene is the most frequent genetic mutation associated with the disease. Scientists of the EU-funded Combat_ALS project are working towards the development of therapeutic tools to counteract the deleterious effects produced by the repeat-containing RNAs resulting from C9ORF72 transcription. A number of chemical agents including antisense oligonucleotides will be tested and their efficacy will be evaluated in cell models and human cerebral organoids.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF-GF - Global FellowshipsCoordinator
28006 Madrid
Spain