RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies
Por:
Mata A, Vila-Planas A, Solsona-Pujol A, Dueña J, Torrents M, Izquierdo-García E, Pastor-Anglada M, Perez-Torras S and Terrazas M
Publicada:
1 sep 2024
Ahead of Print:
1 jul 2024
Resumen:
Combined therapies play a key role in the fight against complex pathologies, such as cancer and related drugresistance issues. This is particularly relevant in targeted therapies where inhibition of the drug target can be overcome by cross-activating complementary pathways. Unfortunately, the drug combinations approved to date -mostly based on small molecules- face several problems such as toxicity effects, which limit their clinical use. To address these issues, we have designed a new class of RNase H-sensitive construct (3ASO) that can be disassembled intracellularly upon cell entry, leading to the simultaneous release of three different therapeutic oligonucleotides (ONs), tackling each of them the mRNA of a different protein. Here, we used Escherichia coli RNase H1 as a model to study an unprecedented mode of recognition and cleavage, that is mainly dictated by the topology of our RNA & sdot;DNA-based hybrid construct. As a model system for our technology we have created 3ASO constructs designed to specifically inhibit the expression of HER2, Akt and Hsp27 in HER2+ breast cancer cells. These trifunctional ON tools displayed very low toxicity and good levels of antiproliferative activity in HER2+ breast cancer cells. The present study will be of great potential in the fight against complex pathologies involving multiple mRNA targets, as the proposed cleavable designs will allow the efficient single-dose administration of different ON drugs simultaneously.
Filiaciones:
Mata A:
Molecular Pharmacology and Experimental Therapeutics, Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBER EHD), Instituto de Salud Carlos III, Madrid, Spain
Institut de Recerca Sant Joan de Déu (IR SJD-CERCA), Esplugues de Llobregat, Barcelona, Spain
Vila-Planas A:
Department of Inorganic and Organic Chemistry, Organic Chemistry Section, Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
Solsona-Pujol A:
Department of Inorganic and Organic Chemistry, Organic Chemistry Section, Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
BioFrontiers Institute, University of Colorado, Boulder, CO, United States
Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO, United States
Dueña J:
Department of Inorganic and Organic Chemistry, Organic Chemistry Section, Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
Torrents M:
Department of Inorganic and Organic Chemistry, Organic Chemistry Section, Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
Izquierdo-García E:
Department of Inorganic and Organic Chemistry, Organic Chemistry Section, Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
Pastor-Anglada M:
Molecular Pharmacology and Experimental Therapeutics, Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBER EHD), Instituto de Salud Carlos III, Madrid, Spain
Institut de Recerca Sant Joan de Déu (IR SJD-CERCA), Esplugues de Llobregat, Barcelona, Spain
Perez-Torras S:
Molecular Pharmacology and Experimental Therapeutics, Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBER EHD), Instituto de Salud Carlos III, Madrid, Spain
Institut de Recerca Sant Joan de Déu (IR SJD-CERCA), Esplugues de Llobregat, Barcelona, Spain
Terrazas M:
Department of Inorganic and Organic Chemistry, Organic Chemistry Section, Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
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