Antisense Oligonucleotides for Polyomavirus T-Antigen Splicing Control
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Solution Overview
Problem
Current methods for inhibiting polyomavirus replication, particularly in immunosuppressed individuals, are inadequate in effectively modulating the splicing of T-antigen pre-mRNA, which is crucial for regulating virus propagation.
Innovation Solution
Development of antisense oligonucleotides that specifically target splice donor and acceptor sites in polyomavirus T-antigen pre-mRNA, modulating splicing to inhibit virus replication and production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides are designed to target polyomavirus mRNA, then virus replication is inhibited, but the ability to specifically modulate splicing of T-antigen pre-mRNA is insufficient
Solution Approach 1:
The patent applies local quality by designing antisense oligonucleotides with specific sequence compositions that target distinct functional regions of the pre-mRNA. Different oligonucleotide sequences are engineered to bind to splice donor sites, splice acceptor sites, or exon sequences with high specificity, enabling precise modulation of splicing events at localized positions within the T-antigen pre-mRNA molecule.
Solution Approach 2:
The patent employs parameter changes by systematically varying the sequence composition, length, and chemical modifications of antisense oligonucleotides to optimize their binding affinity and splicing modulation efficacy. By adjusting these parameters, the invention achieves enhanced precision in controlling splicing outcomes while maintaining reliable virus replication inhibition.
2Reliability
If antisense oligonucleotides target splice sites in T-antigen pre-mRNA, then splicing is modulated effectively, but the complexity of designing and synthesizing these oligonucleotides increases
Solution Approach 1:
The patent applies segmentation by dividing the T-antigen pre-mRNA target into multiple distinct functional regions (splice donor sites, splice acceptor sites, exon sequences). Separate antisense oligonucleotides are designed for each region, allowing independent optimization and simplifying the overall design process while achieving comprehensive splicing modulation.
Solution Approach 2:
The patent employs universality by developing a platform of antisense oligonucleotides that can be applied across different polyomavirus types (JC virus, BK virus, Merkel cell polyomavirus). The design principles and sequence strategies are made universal, enabling the same methodological approach to effectively modulate splicing in multiple viral contexts despite sequence variations.
3Productivity
If current antisense oligonucleotide methods are used, then some virus replication is inhibited, but T-antigen expression and virus production are not sufficiently reduced
Solution Approach 1:
The patent applies preliminary action by targeting the splicing process at the pre-mRNA stage, before the T-antigen protein is fully expressed. By modulating splicing to generate aberrant or non-functional T-antigen variants, the invention prevents the production of functional virus replication machinery in advance, thereby more effectively reducing both T-antigen expression and subsequent virus production.
Solution Approach 2:
The patent employs preliminary anti-action by designing antisense oligonucleotides that bind to critical splice sites in the T-antigen pre-mRNA, preventing proper splicing and thereby pre-emptively blocking the expression of functional T-antigen. This preliminary interference with the gene expression pathway achieves more reliable suppression of virus production compared to targeting already-translated mRNA.
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 antisense oligonucleotides effectively reduce T-antigen expression and virus production, providing a targeted approach to inhibit polyomavirus replication and propagation.
Implementation Method 1
an antisense oligonucleotide which comprises a sequence that is the reverse complement of a contiguous stretch of at least 12 nucleobases of a polyomavirus large T-antigen pre-mRNA
Data Source
AI summary
The invention relates to antisense molecules and methods for modulating splicing of polyomavirus T antigen pre-mRNA. In one aspect the invention relates to an antisense oligonucleotide 12 to 30, preferably 17, 18, 19 or 20 to 30 nucleobases in length which comprises a sequence that is the reverse complement of a contiguous stretch of at least 12 nucleobases of a polyomavirus T-antigen pre-mRNA and which antisense oligonucleotide can modulate splicing of said T-antigen pre-mRNA in a cell.