Antisense Oligonucleotides for Selective PK-M2 Splicing Modulation
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Solution Overview
Problem
Current antisense compounds are ineffective in selectively modulating the expression of pyruvate kinase M (PK-M) isoforms, particularly in cancer cells, where the PK-M2 isoform is predominantly expressed, limiting their therapeutic potential in cancer treatment.
Innovation Solution
Development of modified oligonucleotides that are complementary to specific regions of the PK-M transcript, including exon 10 and adjacent introns, to inhibit the inclusion of exon 10 and promote the skipping of exon 10, thereby reducing the expression of the PK-M2 isoform and potentially increasing the expression of the PK-M1 isoform.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional antisense compounds are used to modulate PK-M expression, then general PK-M suppression occurs, but selective modulation of PK-M2 isoform is not achieved
Solution Approach 1:
The patent applies local quality by designing antisense oligonucleotides that specifically target the unique sequence of exon 10 in the PK-M2 isoform. By focusing the antisense compound's action on a specific local region (exon 10) that is present only in PK-M2 and not in PK-M1, the invention achieves selective modulation of PK-M2 without affecting PK-M1 expression, thereby resolving the contradiction between selectivity and effectiveness
Solution Approach 2:
The invention segments the PK-M gene expression pathway by targeting a specific exon (exon 10) rather than the entire gene. This segmentation allows differential splicing outcomes where PK-M2 (containing exon 10) is suppressed while PK-M1 (lacking exon 10) remains unaffected, achieving isoform-selective therapy
2Manufacturing precision
If antisense compounds target exon 10 to reduce PK-M2, then PK-M2 expression decreases, but off-target effects on other genes may occur
Solution Approach 1:
The antisense oligonucleotides are designed with high local complementarity to exon 10 sequence, ensuring specific binding only to the intended target. This localized sequence matching minimizes off-target effects while achieving precise PK-M2 suppression
Solution Approach 2:
The patent employs modified oligonucleotide chemistry (such as phosphorothioate backbones and 2'-O-methyl modifications) to enhance binding specificity and stability. These chemical modifications substitute for less specific interactions, reducing off-target effects while maintaining potent target engagement
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified oligonucleotides effectively modulate the splicing of PK-M transcripts, reducing PK-M2 expression and potentially increasing PK-M1 expression, which can lead to therapeutic benefits in cancer treatment, including inducing apoptosis in cancer cells.
Implementation Method 1
oligonucleotides are complementary to a target region of the PK-M transcript comprising exon 10
Data Source
AI summary
The present invention provides compounds comprising oligonucleotides complementary to a pyruvate kinase M transcript. Certain such compounds are useful for hybridizing to a pyruvate kinase M transcript, including but not limited to a pyruvate kinase M transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the pyruvate kinase M transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with cancer.