Overcoming Hypomethylating Agents Toxicity and Non-Specificity Using an Aptamer-Based Strategy to Correct Aberrant DNA Methylation in Myelodysplastic Syndromes
Abstract
Myelodysplastic Syndromes (MDS) are a heterogeneous group of clonal hematopoietic malignancies leading to Acute Myeloid Leukemia (AML) in approximately 30 percent of the cases and the most common acquired bone marrow failure syndrome primarily among the elderly(older than age 65). Abnormal DNA methylation is the dominant mechanism for tumor suppress suppress or gene silencing in the evolution of MDS to AML. However, the causes behind aberrant DNA methylation remain elusive. The currently approved hypomethylating protocols are based on two drugs: Azacitidine (AZA-CR) and Decitabine (AZA-dCR). Unfortunately, cytotoxic and global non-specific demethylation effects limit their clinical application. In this study, we propose to test an innovative RNA aptamer-based approach to target aberrant DNA methylation and achieve gene-specific demethylation. This approach is based on our previous discovery of an RNA-mediated regulation of DNA methylation. We have shown that RNAs interacting with the DNA methyltransferase 1 (DNMT1) DiRs, inhibit its activity in a gene-specific manner. In light of this finding, we have developed RNA aptamers binding and inhibiting DNMT1. Herein, we aim to correct DNA methylation pattern globally and selectively using an RNA based approach. Therefore, two specific aims will be pursued: Aim 1. To reduce global DNA methylation by DNMT1-specific aptamers and Aim 2. To achieve selective demethylation by chimeric DNMT1-specific aptamers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2021
- Accession Number
- AD1146834
Entities
People
- Annalisa Di Ruscio
Organizations
- Beth Israel Deaconess Medical Center