Chimeric RNA Oligonucleotides for Gene-Specific DNMT Targeting
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Solution Overview
Problem
Current demethylating agents for treating myelodysplastic syndrome and cancer cause global, non-specific DNA demethylation, leading to cytotoxic effects and increased tumorogenicity due to their lack of gene-specificity.
Innovation Solution
Development of chimeric RNA oligonucleotides (CROs) that target specific genes by binding to DNA methyltransferases (DNMTs), reducing DNA methylation in a gene-specific manner, and can be administered with pharmaceutically acceptable excipients or combined with histone deacetylase inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If global demethylating agents (azacitidine, decitabine) are used to treat myelodysplastic syndrome, then DNA methylation is reduced, but cytotoxic effects and increased tumorogenicity occur due to non-specific demethylation
Solution Approach 1:
The patent applies local quality by designing RNA oligonucleotides with gene-specific sequences that target only particular methylated genes rather than causing global demethylation. The oligonucleotides contain specific nucleotide sequences complementary to target gene regions, enabling selective binding and demethylation of only those genes, thus maintaining therapeutic efficacy while avoiding off-target cytotoxic effects and tumorogenicity associated with non-specific demethylating agents
Solution Approach 2:
The patent uses RNA oligonucleotides as intermediary molecules that mediate between the demethylating agent and the target DNA. These RNA oligonucleotides first bind to the target gene sequence, then recruit DNMT1 to the specific location, acting as a guided intermediary that delivers demethylation activity precisely to the intended target while preventing random or global demethylation events that cause harm
2Object-affected harmful factors
If non-nucleoside inhibitors of DNA methylation are used, then side effects are reduced, but demethylation efficiency decreases and global demethylation still occurs
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure and properties of the oligonucleotides, including using modified nucleotides (such as 2'-O-methyl nucleotides, locked nucleic acids) to enhance binding affinity, stability, and specificity. These parameter modifications allow the oligonucleotides to achieve high demethylation efficiency while maintaining low toxicity, overcoming the trade-off between efficiency and side effects observed with conventional non-nucleoside inhibitors
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The CROs effectively reduce DNA methylation of specific genes, potentially minimizing side effects and enhancing therapeutic outcomes for conditions like cancer by providing a gene-specific approach to demethylation.
Implementation Method 1
the oligonucleotide includes a sequence of about 15 to about 30 nucleotides having at least 80% complementarity to a portion of an extra-coding RNA of the gene, and where the synthesized RNA binds to the extra-coding RNA to form a complex
Implementation Method 2
the complex binds to a DNMT to reduce DNA methylation of the gene
Data Source
AI summary
The present invention relates to chimeric RNA oligonucleotides that are single-stranded oligonucleotides. These compounds are capable of targeting particular genes and reducing DNA methyltransferase activity. Accordingly, these compounds are particularly useful in the treatment of disease associated with aberrant DNA methyltransferase activity, such as cancer or a genetic disorder.