Descrizione del progetto
Gli RNA lunghi non codificanti come potenziali bersagli terapeutici nelle malattie vascolari
Le terapie basate sugli acidi nucleici stanno emergendo come opzioni terapeutiche per molte malattie. La maggior parte del genoma umano è trascritta in RNA non codificanti, tra cui più di 15 000 RNA non codificanti lunghi (lncRNA). Il targeting degli lncRNA tramite strategie di interferenza a RNA offre l’opportunità di modulare i processi cellulari. L’obiettivo del progetto LongTx, finanziato dal CER, è identificare gli lncRNA coinvolti nello sviluppo delle malattie vascolari come potenziali bersagli terapeutici. La profilazione del tessuto umano malato di pazienti con patologie della carotide, ictus e aneurisma dell’aorta addominale ha portato all’identificazione di due lncRNA adatti. Gli obiettivi del progetto sono lo studio di questi lncRNA nel modello preclinico arterie-on-chip e in vivo in modelli animali geneticamente modificati, concentrandosi sulla somministrazione efficiente di oligonucleotidi antisenso inibitori per colpire questi trascritti.
Obiettivo
The perception that RNAs are passive carriers of genetic information has been overturned. Due to the diverse targeting abilities and extensive research in RNA modification and delivery systems, nucleic acid-based therapies have emerged as suitable treatment options for many diseases. Targeting RNAs offers opportunities to modulate numerous cellular processes, including those linked to the large portion of ‘undruggable’ proteins. Currently approved protein-targeted therapies interact with <700 gene products, meaning that only 0.05% of the human genome is presently utilized for treatment. On the contrary, a large fraction of the human genome (>70%) is transcribed into non-coding RNAs. Humans produce more than 15.000 long non-coding RNAs (lncRNA), with a substantial subset of these likely being ‘druggable’ via RNA interference strategies, such as antisense oligonucleotides and siRNAs. In my current LongTx proposal, we aim at identifying suitable lncRNAs with relevance to vascular disease development and progression. To be successful, we made sure that we have identified suitable lncRNAs by profiling diseased human tissue from patients with carotid artery disease and stroke, as well as abdominal aortic aneurysms. Both diseases are currently being treated with suboptimal surgical interventions, and the growing affected patient population would tremendously benefit from novel treatment strategies that enable stabilization of advanced vulnerable atherosclerotic lesions, and also limit the risk for acute aortic ruptures and dissections. The two lncRNAs we have identified in preliminary studies using single-cell, bulk, and spatial transcriptomics are called CRNDE and NKILA. We propose to study these lncRNAs in disease-relevant preclinical in vitro (arteries-on-chips) and in vivo (genetically mutated mice and mini-pigs) models, with a strong focus on novel local delivery concepts for antisense oligonucleotide inhibitors that site-specifically target both transcripts.
Campo scientifico
- medical and health sciencesclinical medicineangiologyvascular diseases
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesclinical medicinesurgerysurgical procedures
- medical and health sciencesbasic medicineneurologystroke
- natural sciencesbiological sciencesgeneticsRNA
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
81675 Muenchen
Germania