Session: 802. Chemical Biology and Experimental Therapeutics: Poster I
Hematology Disease Topics & Pathways:
Diseases, Therapies, MDS, Biological Processes, epigenetics, Myeloid Malignancies
In the past decades two nucleoside-based compounds, 5-azacytidine and 5-aza 2’-deoxycytidine have been extensively tested to reduce global DNA methylation levels and received approval by the U.S. Food and Drug Administration (FDA) for the treatment of MDS. Both drugs have been used as the frontline therapy for the management of higher-risk-to-transform MDS, that are ineligible for more aggressive treatment such as: allogenic transplants and standard chemotherapy. Unfortunately, cytotoxic and global non-specific demethylation effects, have limited their clinical application, revealing the need for smarter and safer epigenetic drugs.
Nucleic-acid aptamers are a new class of specific targeting molecules and represent high affinity ligands and potential antagonists of disease-associated proteins.
Herein, we present an innovative RNA aptamer-based approach to target DNMT1 function by translating the inherent neutralizing properties of RNA (Di Ruscio, Ebralidze et al. Nature, 2013, 503(7476):371-6) into an aptamer platform. Through a combinatorial chemistry strategy named SELEX (Systematic Evolution of Ligands by EXponential enrichment) (Mercier, Dontenwill et al. 2017), we shortlisted the most specific DNMT1-neutralizing RNA aptamers. These molecules display high specificity and serum stability and reveal strong structural affinity in targeting DNMT1, by molecular modelling and dynamic simulations. Foremost, we found that the selected aptamers specifically inhibit DNMT1 enzymatic activity both in vitro and in cells, thus impairing cell viability and leading to global demethylation.
Collectively, this study provides a proof-of-concept for the generation of the first RNA-based epigenetic therapy as well as an attractive and scalable tool of precision medicine. Such a tool will overcome the toxicity of in-use demethylating protocols and greatly improve care and treatment of patients with MDS and other disease triggered by aberrant DNA methylation.
Disclosures: No relevant conflicts of interest to declare.
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