Small-Molecule Splicing Regulation Without Complex Nucleic Acid Delivery
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Solution Overview
Problem
Current therapies to modulate RNA expression, such as oligonucleotide targeting and gene therapy, face unique challenges, necessitating the development of small molecule compounds that target splicing to regulate alternative splicing patterns in a tissue-specific or development stage-specific manner.
Innovation Solution
Development of compounds of Formula (I) and (II) that bind or form complexes with nucleic acids or proteins involved in the splicing machinery, altering splicing events and modulating the expression of genes, including increasing or decreasing splicing at splice sites to affect the production of RNA or protein levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligonucleotide targeting or gene therapy is used to modulate RNA expression, then RNA expression can be modulated, but the therapy faces unique challenges including delivery complexity and immunogenicity
Solution Approach 1:
The patent replaces complex oligonucleotide delivery systems with small molecule compounds that can be administered through conventional oral or parenteral routes. The small molecules directly target splicing regulatory proteins, eliminating the need for complex nucleic acid delivery mechanisms while achieving the same RNA expression modulation effect.
Solution Approach 2:
The patent employs small molecule compounds that are chemically synthesized and can be produced more easily and cost-effectively than oligonucleotide therapies. These small molecules serve as disposable therapeutic agents that achieve their effect and are metabolized without requiring complex storage or handling infrastructure.
2Adaptability or versatility
If current oligonucleotide or gene therapy approaches are used, then RNA expression can be modulated, but tissue-specific or development stage-specific regulation is difficult to achieve
Solution Approach 1:
The patent designs small molecule compounds with specific chemical structures that target splicing regulatory proteins expressed in particular tissues or developmental stages. By modifying molecular structure and pharmacokinetic properties, the compounds achieve localized action at specific anatomical sites or developmental windows, enabling tissue-specific splicing regulation without complex delivery systems.
Solution Approach 2:
The patent utilizes structure-activity relationship studies to optimize small molecule parameters including lipophilicity, molecular weight, and functional groups to achieve desired tissue distribution and specificity. By adjusting these chemical parameters, the compounds can be fine-tuned for specific tissue targeting and developmental stage selectivity.
Data Source
AI summary
The present disclosure features compounds and related compositions that, inter alia, modulate nucleic acid splicing, e.g., splicing of a pre-mRNA, as well as methods of use thereof.