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1551 An Engineered RNA Platform to Neutralize DNMT1 Function and Control DNA Methylation for Myelodysplastic Syndrome

Program: Oral and Poster Abstracts
Session: 802. Chemical Biology and Experimental Therapeutics: Poster I
Hematology Disease Topics & Pathways:
Diseases, Therapies, MDS, Biological Processes, epigenetics, Myeloid Malignancies
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Carla Lucia Esposito1*, Ida Autiero2,3*, Mahmoud Adel Bassal, PhD4,5*, Sandomenico Annamaria3*, Simone Ummarino4,6*, Marta Borchiellini7,8*, Menotti Ruvo3,9*, Silvia Catuogno1*, Alexander Ebralidze, PhD4,6*, Vittorio De Franciscis1* and Annalisa Di Ruscio, MD, PhD7,10

1Institute for Experimental Endocrinology and Oncology "Gaetano Salvatore", CNR, Naples, Italy
2Molecular Horizon, Bettona, Italy
3Institute of Biostructures and Bioimaging, CNR, Naples, Italy
4Harvard Stem Cell Institute, Harvard Medical School, Boston
5Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
6Harvard Medical School Initiative for RNA Medicine, Boston
7Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
8Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
9Anbition srl, Naples, Italy
10Beth Israel Deaconess Medical Center, Boston, MA

DNA methylation is a major signature involved in the regulation of gene expression. Numerous studies have established a link between aberrant DNA methylation and cancer (Herman and Baylin 2003, Baylin and Jones 2011, Feinberg 2018). Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic malignancies, characterized by ineffective hematopoiesis, cytopenia and risk of progression to acute myeloid leukemia (AML) in approximately 30% of the cases (Khan, Vale et al. 2013, Arber, Orazi et al. 2016). Abnormal DNA methylation is considered the molecular lesion leading to tumor suppressor gene silencing and clonal variation in MDS and evolution to AML (Figueroa, Skrabanek et al. 2009, Jiang, Dunbar et al. 2009, Feinberg 2018).

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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