Small Molecule Splicing Modulators for Pre-mRNA Steric Barriers

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Solution Overview

Problem

Current therapeutic approaches for modulating mRNA expression, such as gene therapy and oligonucleotide therapies, face challenges including unfavorable pharmacokinetics, lack of oral bioavailability, poor blood-brain-barrier penetration, and structural limitations due to complex pre-mRNA secondary and tertiary structures, limiting their effectiveness in treating RNA-mediated diseases.

Innovation Solution

Development of small molecule splicing modulators (SMSMs) that bypass the structural and steric hindrances of oligonucleotides by directly targeting the RNA transcriptome, providing a novel therapeutic approach to modulate splicing processes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If oligonucleotide therapies are used to modulate mRNA expression, then splicing can be controlled, but pharmacokinetics are unfavorable and oral bioavailability is lacking

Engineering Contradiction:

Improvesplicing controlVSAvoidoral bioavailability

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent replaces oligonucleotide-based mechanisms (which rely on canonical base pairing and have poor pharmacokinetics) with small molecule mechanisms that interact with RNA through non-canonical binding modes, thereby achieving splicing control with improved oral bioavailability and pharmacokinetic properties

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent changes the fundamental parameters of the therapeutic agent: transitioning from large oligonucleotide molecules (with poor membrane permeability) to small molecule compounds (with improved cellular uptake and oral bioavailability), while maintaining the ability to modulate splicing through different binding mechanisms

Inventive Principle:

Principle #35Parameter changes

2Reliability

If oligonucleotide therapies are used to target pre-mRNA, then splicing modulation is achieved, but structural and steric hindrances from complex pre-mRNA secondary and tertiary structures limit effectiveness

Engineering Contradiction:

Improvesplicing modulationVSAvoidstructural and steric hindrances

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent replaces the oligonucleotide base-pairing mechanism (which is hindered by RNA secondary/tertiary structures) with small molecule binding mechanisms that can access and bind to RNA through alternative interactions, overcoming the steric barriers posed by complex RNA folding

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent introduces small molecules as intermediary agents that can penetrate and bind to the complex three-dimensional structure of pre-mRNA, serving as mediators that overcome the steric hindrances that prevent direct oligonucleotide access to target sites

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If gene therapy or genome editing is used to act upstream of transcription, then mRNA expression is changed, but technical and regulatory challenges arise

Engineering Contradiction:

ImprovemRNA expression changeVSAvoidtechnical and regulatory challenges

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent acts at the post-transcriptional level (on mature mRNA or pre-mRNA) rather than requiring upstream genomic modifications, thereby achieving mRNA expression changes through splicing modulation without the complexity and regulatory burden of gene therapy or genome editing approaches

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS12522597B2Methods and compositions for modulating splicing

Publication Date: 2026.01.13 SKYHAWK THERAPEUTICS INC

AI summary

Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, pharmaceutical compositions comprising the same, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.