Descripción del proyecto
Moléculas de ARN no codificante de cadena larga como posibles dianas terapéuticas en las enfermedades vasculares
Las terapias basadas en ácidos nucleicos están surgiendo como opciones terapéuticas para muchas enfermedades. La mayor parte del genoma humano se transcribe en ARN no codificante, incluidas más de 15 000 moléculas de ARN no codificante de cadena larga (ARNncl). Dirigirse al ARNncl mediante estrategias de interferencia de ARN ofrece oportunidades para modular procesos celulares. El objetivo del proyecto LongTx, financiado por el CEI, es identificar las moléculas de RNAncl implicadas en el desarrollo de enfermedades vasculares como posibles dianas terapéuticas. El perfilado del tejido humano enfermo procedente de pacientes con enfermedad de la arteria carótida, ictus y aneurismas aórticos abdominales condujo a la identificación de dos moléculas de RNAncl adecuadas. Los objetivos del proyecto son estudiar estas RNAncl en el modelo preclínico de arterias-en-chips e «in vivo» en modelos animales modificados genéticamente, centrándose en la administración eficiente de inhibidores de oligonucleótidos antisentido dirigidos a estos transcritos.
Objetivo
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.
Ámbito científico
- medical and health sciencesclinical medicineangiologyvascular diseases
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesclinical medicinesurgerysurgical procedures
- medical and health sciencesbasic medicineneurologystroke
- natural sciencesbiological sciencesgeneticsRNA
Palabras clave
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-ERC - HORIZON ERC GrantsInstitución de acogida
81675 Muenchen
Alemania