Phosphorothioated Oligonucleotide Conjugates for Selective STAT3 Targeting
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Solution Overview
Problem
Existing cancer treatments using antisense oligonucleotides face challenges in targeted delivery and immune system sensitivity, particularly for conditions like acute myeloid leukemia and prostate cancer, due to the lack of cell selectivity and enzymatic activity of transcription factors such as STAT3, necessitating non-pharmacologic approaches.
Innovation Solution
Development of phosphorothioated oligodeoxynucleotides conjugated with short-activating RNA (saRNA) or antisense oligonucleotides (ASO) to enhance or suppress gene expression, specifically targeting C/EBPα and STAT1-STAT6, for treating cancers like AML and prostate cancer, with enhanced stability and immune response stimulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If traditional antisense oligonucleotides are used to target transcription factors like STAT3, then gene expression can be suppressed, but cell selectivity is limited and delivery efficiency is poor
Solution Approach 1:
The patent combines phosphorothioated oligodeoxynucleotides with targeting moieties (such as peptides or antibodies) to create composite oligonucleotide conjugates. This composite structure provides both the gene-silencing capability of antisense oligonucleotides and the cell-specific targeting ability of the attached moiety, thereby improving cell selectivity while maintaining delivery efficiency through systemic administration
Solution Approach 2:
The patent introduces phosphorothioated oligodeoxynucleotides as intermediaries that bridge the gap between traditional antisense oligonucleotides and cell-specific targets. These phosphorothioated conjugates serve as mediators that can be systemically administered and selectively delivered to target cells through their attached targeting moieties, overcoming the delivery inefficiency of traditional antisense oligonucleotides
2Reliability
If phosphorothioated oligodeoxynucleotides are conjugated to enhance stability and enable systemic administration, then delivery is improved, but device complexity increases
Solution Approach 1:
The patent applies phosphorothioate modifications locally at specific positions within the oligonucleotide sequence rather than uniformly throughout. This localized modification strategy enhances stability and enables systemic administration while minimizing the overall complexity of the conjugate structure by concentrating modifications only where needed for stability and targeting
3Productivity
If short-activating RNAs are used to enhance gene expression, then therapeutic effect is improved, but immunogenicity increases
Solution Approach 1:
The patent modifies the chemical parameters of short-activating RNAs by incorporating phosphorothioate modifications and other chemically stable nucleotide analogs. These parameter changes reduce the immunogenicity of the RNA molecules while preserving their ability to enhance gene expression, making them suitable for systemic administration and repeated dosing
Data Source
AI summary
The present disclosure relates to an isolated compound including a phosphorothioated oligodeoxynucleotide (ODN) sequence conjugated to a short-activating RNA (saRNA) or an antisense oligonucleotide sequence (ASO), compositions of such a compound, and method of treatment of cancer and autoimmune diseases (with or without stimulating an immune response), method of immune stimulation, method of activating CEBPA, and method of reducing activity of STAT transcription factor, by one of the disclosed compounds or compositions.