Splice-Switching Oligonucleotides Targeting TE-Driven LIN28B Isoforms
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Solution Overview
Problem
Current cancer therapies lack effective targeting of the transposable-element (TE)-driven isoform of LIN28B, a tumor-specific oncogene associated with poor prognosis in various cancers, as existing treatments focus on canonical forms rather than TE-driven variants.
Innovation Solution
Development of splice-switching oligonucleotides (SSOs) specifically designed to target the TE-driven isoform of LIN28B, such as AluJb-LIN28B, by binding to exon-intron or intron-exon junctions, using sequences like SEQ ID NO: 1 or SEQ ID NO: 2, and incorporating chemical modifications like 2′-O-methoxyethyl and phosphorothioate internucleotide linkages to reduce mRNA and protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing cancer therapies target canonical LIN28B forms, then general cancer treatment is provided, but TE-driven isoform expression remains untreated leading to poor prognosis
Solution Approach 1:
The SSOs are designed with specific sequence complementarity to target only the TE-driven isoform of LIN28B (containing AluJb insertion) while sparing the canonical LIN28B isoform. This local sequence specificity allows differential treatment of cancer cells expressing the TE-driven isoform versus normal cells or cancer cells with only canonical isoform expression.
Solution Approach 2:
The invention segments the LIN28B gene expression into distinguishable isoforms based on the presence of TE insertions. By designing SSOs that specifically recognize sequences unique to the TE-driven isoform (such as exon-intron junctions containing AluJb), the therapy can selectively target this specific segment of gene expression without affecting other LIN28B isoforms.
2Object-affected harmful factors
If SSOs are designed to target TE-driven isoform specifically, then selective cancer cell killing is achieved, but off-target effects on canonical LIN28B expression must be avoided
Solution Approach 1:
The SSO sequences are designed to match specifically with regions unique to the TE-driven LIN28B isoform, such as exon-intron junctions containing the AluJb transposable element insertion. This local sequence matching ensures that only cells expressing the TE-driven isoform are affected, while cells expressing only the canonical LIN28B isoform remain unaffected.
Solution Approach 2:
The SSOs act as intermediary molecules that bridge the specific sequence features of the TE-driven isoform (such as altered splice junctions) and the therapeutic effect of reduced LIN28B expression. By targeting these intermediate sequence features rather than the protein product directly, the therapy achieves isoform-specificity.
3Reliability
If chemical modifications are incorporated into SSOs, then stability and activity are improved, but manufacturing complexity increases
Solution Approach 1:
The SSOs incorporate chemical modifications such as phosphorothioate backbone linkages and 2′-O-methoxyethyl sugar modifications. These parameter changes in the chemical structure of the oligonucleotide improve resistance to nucleases and enhance binding stability to the target RNA, while the modifications are applied using established chemical synthesis methods.
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 SSOs selectively reduce cancer cell viability while sparing normal cells, demonstrating potent activity against AluJb-LIN28B-expressing cancer cells without affecting canonical LIN28B-expressing cells, thereby offering a novel therapeutic approach for cancers driven by TE-derived LIN28B expression.
Implementation Method 1
administering to the subject a splice-switching oligonucleotide (SSO) targeted to a nucleic acid encoding a transposable element (TE)-driven isoform of LIN28B
Implementation Method 2
the SSO is targeted to an exon-intron junction or an intron-exon junction of the TE-driven isoform of LIN28B
Data Source
AI summary
The present disclosure provides for splice-switching oligonucleotides (SSOs) targeted to a nucleic acid encoding a transposable element (TE)-driven isoform of LIN28B, such as AluJb-LIN28B. The SSOs may be targeted to an exon-intron or intron-exon junction to inhibit splicing and expression of the TE-driven isoform of LIN28B. Methods of treating cancer, particularly cancers expressing AluJb-LIN28B, comprising administering the SSOs are also provided.