Investigation of RNA-misprocessing in neurological diseases for the development of novel diagnostic and therapeutic approaches

A Velasco(1) O Arnold(1) X Bujanda(1) A Rubio(1) M Garcia-Puga(1) L Blazquez(1)

1:Biodonostia Institute

RNA-processing is the molecular mechanism by which precursor messenger RNAs (pre-mRNAs) are capped, spliced and polyadenylated. It is a fundamental process that ensures a correct gene expression pattern and, as such, its misregulation has been implicated in a variety of human diseases. 

In the lab, we are currently investigating RNA-misprocessing in cellular models, tissues and biofluids of patients with neurodegenerative diseases in order to develop: (i) personalized antisense RNA-based therapeutic strategies using RNA-targeting CRISPR-dCas13 system, (ii) sensitive RNA detection methods that could serve as future biomarkers. 

In Frontotemporal dementia, we have combined bioinformatic and experimental approaches to characterize the molecular mechanism of a non-coding mutation in GRN gene, which leads to an aberrant splicing pattern that causes GRN mRNA degradation and progranulin haploinsufficiency. We are currently exploiting CRISPR-dCas13 RNA targeting system in order to identify sequences in GRN pre-mRNA whose targeting using antisense RNAs would restore GRN reading-frame. Based on this concept, we would like to develop a future personalized therapeutic approach for patients with this mutation.

Another aim in the lab is to perform and exploit computational analysis of RNA-seq data in order to investigate RNA-misprocessing events relevant for disease etiology and to develop sensitive RNA quantification methods which can be used as future biomarkers of neurological diseases. Specifically, we are developing targeted RNA-sequencing approaches to quantify cryptic polyadenylation events in STMN2 and HTT genes in disease models of TDP43-proteinopathies and Huntington’s disease.