Small-Molecule Splicing Modulators for Brain-Penetrant RNA Targeting
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Solution Overview
Problem
Current therapeutic approaches for modulating mRNA splicing, such as gene therapy, genome editing, and oligonucleotide therapies, face challenges including unfavorable pharmacokinetics, lack of oral bioavailability, and difficulty penetrating the blood-brain barrier, which limits their effectiveness in treating neurological diseases and brain cancers, and they often fail to access the cytosol and nucleus where targets are located.
Innovation Solution
Development of small molecule splicing modulators (SMSMs) that can modulate splicing by binding to RNA structures, overcoming structural and steric hindrances, and providing a novel therapeutic approach to treat RNA-mediated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligonucleotide therapies are used to modulate mRNA splicing, then splicing modulation capability is achieved, but pharmacokinetics are unfavorable and blood-brain barrier penetration is limited
Solution Approach 1:
The patent changes the fundamental chemical parameter of the therapeutic agent from oligonucleotide (nucleic acid-based) to small molecule compound. This parameter change enables the compound to achieve both splicing modulation capability and favorable pharmacokinetics including oral bioavailability and blood-brain barrier penetration, resolving the contradiction between therapeutic efficacy and delivery limitations
Solution Approach 2:
The patent replaces the canonical base pairing mechanism (mechanical/structural recognition) of oligonucleotides with a small molecule binding mechanism that targets RNA secondary and tertiary structures. This substitution allows the therapeutic agent to modulate splicing while achieving small molecule pharmacokinetic properties including better tissue penetration and oral bioavailability
2Measurement precision
If oligonucleotide therapies are designed to anneal to target pre-mRNA, then sequence-specific binding is achieved, but structural complexity of pre-mRNA and steric hindrance limit potency and efficacy
Solution Approach 1:
The patent transitions from targeting linear sequence (one-dimensional) to targeting RNA secondary and tertiary structures (two and three-dimensional). Small molecule compounds can bind to complex folded RNA structures including stem-loops, pseudoknots, and other three-dimensional motifs, achieving specific binding without being limited by linear sequence accessibility or steric hindrance from protein binding elements
Solution Approach 2:
The patent applies local quality by designing small molecule compounds that target specific local structural features of pre-mRNA (such as particular stem-loop configurations or junction regions) rather than requiring extensive linear sequence complementarity. This allows potent and specific binding to critical splicing regulatory elements while avoiding regions obscured by complex higher-order structure or protein binding
3Ease of operation
If gene therapy or genome editing is used to influence DNA code, then upstream control of mRNA expression is achieved, but technical and regulatory challenges increase
Solution Approach 1:
The patent extracts the therapeutic action from the nucleus (where gene therapy and genome editing operate) and places it in the cytoplasm/nucleus interface where splicing occurs. By targeting the splicing process itself rather than requiring permanent genetic modification, the invention achieves upstream control of mRNA expression with simpler, reversible, and more regulatable small molecule therapy rather than complex gene editing approaches
Data Source
AI summary
Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.