Oligonucleotides Upregulating UTRN Expression via PRC2 Targeting
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Solution Overview
Problem
Current treatments for muscular dystrophies, such as Duchenne and Becker muscular dystrophy, and myotonic dystrophy, are inadequate in addressing the underlying genetic deficiencies, particularly the reduced expression of Utrophin (UTRN), which contributes to muscle degeneration and related symptoms.
Innovation Solution
Development of single-stranded oligonucleotides that target Polycomb repressive complex 2 (PRC2)-associated regions of the UTRN gene to upregulate Utrophin expression, using specific sequences and chemistries to enhance gene expression and bypass PRC2-mediated repression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for muscular dystrophies, then disease symptoms are managed, but the underlying genetic deficiencies (reduced UTRN expression) are not addressed
Solution Approach 1:
The patent extracts and targets the specific mechanism of PRC2-mediated repression of the UTRN gene. By identifying and isolating the PRC2-associated region in the UTRN gene promoter, the invention can specifically disrupt this repressive mechanism through oligonucleotide therapy, thereby addressing the root genetic deficiency rather than merely managing symptoms.
Solution Approach 2:
The patent employs parameter changes by using chemically modified oligonucleotides with specific sequences that bind to the PRC2-associated region. These modifications (such as phosphorothioate backbones, 2'-O-methyl modifications) alter the physical and chemical parameters of the oligonucleotide to enhance its stability, binding affinity, and ability to disrupt PRC2-mediated repression, thereby achieving reliable upregulation of UTRN expression.
2Reliability
If UTRN expression is increased to treat muscular dystrophies, then muscle degeneration is reduced, but the mechanism of PRC2-mediated repression must be overcome
Solution Approach 1:
The patent applies preliminary anti-action by designing oligonucleotides that preemptively bind to and disrupt the PRC2 complex before it can repress the UTRN gene. The oligonucleotides are designed to interfere with PRC2's ability to recruit histone methyltransferase activity to the UTRN promoter, thereby preventing repression rather than reversing it after occurrence.
Solution Approach 2:
The patent uses oligonucleotides as intermediary molecules that mediate between the therapeutic goal (upregulating UTRN) and the obstructing mechanism (PRC2 repression). These intermediary oligonucleotides bind to the PRC2-associated region, disrupting the interaction between PRC2 and the UTRN promoter, thereby enabling UTRN expression without directly attacking the harmful PRC2 complex itself.
3Reliability
If oligonucleotides are designed to target PRC2-associated regions, then UTRN expression is upregulated, but specific sequence requirements and chemistries must be optimized
Solution Approach 1:
The patent applies local quality by designing oligonucleotides with specific local characteristics tailored to bind the PRC2-associated region. The oligonucleotides have specific sequence compositions (rich in certain nucleotides), structural features (such as hairpin formations), and chemical modifications concentrated in regions that interact with PRC2, thereby achieving precise and reliable disruption of repression with optimized manufacturing parameters.
Data Source
AI summary
Aspects of the invention provide single stranded oligonucleotides for activating or enhancing expression of UTRN. Further aspects provide compositions and kits comprising single stranded oligonucleotides for activating or enhancing expression of UTRN. Methods for modulating expression of UTRN using the single stranded oligonucleotides are also provided. Further aspects of the invention provide methods for selecting a candidate oligonucleotide for activating or enhancing expression of UTRN.