Oligonucleotide Therapeutics for Neuromuscular Disease Splicing Correction
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for Myotonic Dystrophy Type 1 (DM1) lack effective solutions to address the progressive muscle wasting and weakness caused by genetic mutations leading to mis-splicing of transcripts and haploinsufficiency of the DMPK protein, with no cure available.
Innovation Solution
Development of compounds that bind to mRNA sequences containing CUG repeats, disrupting sequestration of splice regulators like MBNL1 and MBNL2, thereby normalizing splicing and reducing disease-causing transcript levels, including oligomeric sequences and peptide nucleic acid structures that penetrate cells and nuclei to correct splicing defects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligomeric compounds are administered to treat DM1, then splicing defects are corrected and muscle function improves, but the compounds must penetrate cell membranes and nuclear envelopes which limits bioavailability
Solution Approach 1:
The patent employs cell-permeable peptides and nuclear localization signals as intermediary carriers that facilitate the transport of oligomeric compounds through cell membranes and into the nucleus. These intermediaries temporarily associate with the therapeutic oligomers, enabling them to cross biological barriers that would otherwise prevent nuclear access and splicing correction.
2Reliability
If high doses of oligomeric compounds are used to ensure sufficient nuclear penetration, then splicing correction is improved, but off-target effects and toxicity increase
Solution Approach 1:
The patent designs oligomeric compounds with localized functional regions: one end contains the splicing-modulating sequence that specifically binds to target pre-mRNA, while the other end contains cell-penetrating or nuclear-targeting moieties. This spatial differentiation ensures that the therapeutic action is concentrated at the nuclear splicing sites while minimizing off-target interactions in the cytoplasm or extracellular space.
Solution Approach 2:
The use of targeted delivery systems acts as an intermediary that selectively transports the oligomeric compound to the intended nuclear destination. This targeted approach reduces the overall dose required by ensuring efficient delivery to the site of action, thereby minimizing off-target effects and systemic toxicity associated with higher doses.
3Reliability
If oligomeric compounds with high nuclear affinity are designed to maximize splicing correction, then therapeutic effect is improved, but cellular uptake and endosomal escape become limiting factors
Solution Approach 1:
The patent merges multiple functional components into a single oligomeric compound structure: the splicing-modulating sequence, cell-penetrating peptide, and nuclear localization signal are integrated into one molecule. This consolidation ensures that the compound possesses all necessary functions for successful delivery and action, simplifying the overall therapeutic approach while maintaining high nuclear affinity for effective splicing correction.
Data Source
AI summary
The present disclosure relates to compounds useful for the detection or modulation of target nucleic acids, including DNA and RNA. The present disclosure further relates to methods for treatment of trinucleotide repeat disorders, which can include administration of oligonucleotid analogues that can bind pathogenic nucleotide repeats in DNA or RNA.