Antisense Oligonucleotides Modulating Fibronectin Splicing
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Solution Overview
Problem
Current treatments for fibrotic disorders, such as renal fibrosis, are inadequate in modulating fibronectin protein isoforms, particularly in reducing the extra type III domain A (EDA) containing fibronectin, which contributes to fibrosis formation.
Innovation Solution
Development of modified oligonucleotides that are complementary to specific regions of the fibronectin transcript, including the EDA exon, introns adjacent to the EDA exon, to inhibit the inclusion of the EDA exon and promote its skipping, thereby increasing the production of EDA-negative fibronectin protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for fibrotic disorders are used, then general fibrosis management is maintained, but they are inadequate in modulating fibronectin protein isoforms and reducing EDA-containing fibronectin
Solution Approach 1:
The invention divides the fibronectin pre-mRNA into distinct functional regions (exons and introns) and applies specific antisense oligonucleotides to target different segments. By designing ASOs that bind to specific intronic regions flanking the EDA exon, the treatment selectively modulates splicing of this particular exon while leaving other fibronectin isoforms unaffected, thereby achieving isoform-specific modulation that current treatments cannot accomplish.
Solution Approach 2:
The invention applies local quality by targeting specific local regions of the fibronectin transcript (introns adjacent to the EDA exon) with antisense oligonucleotides. This localized targeting ensures that only the EDA-containing isoform is affected, while maintaining the production of other fibronectin isoforms, thus improving versatility in modulating specific protein isoforms without broadly suppressing all fibronectin expression.
2Reliability
If antisense compounds are designed to target the EDA exon, then EDA-containing fibronectin is reduced, but this may affect overall fibronectin expression and splicing regulation
Solution Approach 1:
The invention extracts the regulatory control from the EDA exon itself and places it in the flanking intronic regions. By designing ASOs that target introns adjacent to the EDA exon rather than the exon itself, the treatment isolates the effect to only the EDA isoform's splicing regulation, preventing off-target effects on other fibronectin isoforms or splicing events, thus reducing harmful side effects while maintaining reliable EDA-fibronectin reduction.
Solution Approach 2:
The invention uses the intronic regions as intermediary targets instead of directly targeting the EDA exon. These intronic regions serve as mediators that, when bound by ASOs, indirectly regulate the inclusion/exclusion of the EDA exon without directly interfering with the exon sequence itself. This intermediary approach minimizes off-target effects on other splicing events and fibronectin expression while achieving the desired reduction in EDA-containing protein.
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 reduce the levels of EDA-positive fibronectin protein, potentially mitigating fibrosis by altering splicing patterns and promoting the production of EDA-negative fibronectin, which can help in reversing fibrotic changes in cells.
Implementation Method 1
modified oligonucleotides that are complementary to specific regions of the fibronectin transcript, including the EDA exon, introns adjacent to the EDA exon
Implementation Method 2
Alternative splicing of fibronectin pre-mRNA leads to the creation of fibronectin mRNA having a different combination of exons, which in turn leads to the creation of several isoforms of fibronectin protein
Data Source
AI summary
The present invention provides compounds comprising oligonucleotides complementary to a fibronectin transcript. Certain such compounds are useful for hybridizing to a fibronectin transcript, including but not limited to a fibronectin transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the fibronectin transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with fibrosis. In certain embodiments, such compounds are used to treat one or more symptoms associated with renal fibrosis.