Antisense Oligonucleotides Restore CFTR Function

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current treatments for cystic fibrosis, particularly those involving mutations that cause premature termination codons, are less effective due to mRNA instability and lack of the natural C-terminal portion of the CFTR protein, necessitating a more effective therapeutic strategy to restore CFTR function.

Innovation Solution

The use of antisense oligonucleotides (ASOs) that induce specific pre-mRNA splicing events in CFTR gene transcripts to skip exons with mutations, restoring the open reading frame and increasing the levels of correctly localized CFTR protein at the plasma membrane, thereby enhancing protein function.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used for cystic fibrosis patients with premature termination codons, then treatment simplicity is maintained, but CFTR protein function is not effectively restored due to mRNA instability and missing C-terminal portion

Engineering Contradiction:

ImproveCFTR protein function restorationVSAvoidtreatment complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent uses antisense oligonucleotides as intermediary molecules that bind to pre-mRNA to modulate splicing events. These ASOs act as mediators between the genetic material and the splicing machinery, enabling precise control over which exons are included or excluded in the final mRNA transcript, thereby restoring CFTR function without directly modifying the gene itself

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The treatment targets pre-mRNA before it is processed into mature mRNA. By acting at this preliminary stage, the antisense oligonucleotides can prevent the formation of defective mRNA transcripts containing premature termination codons, ensuring that only correctly spliced, functional mRNA is translated into CFTR protein

Inventive Principle:

Principle #10Preliminary action

2Reliability

If antisense oligonucleotides are used to induce specific splicing events, then CFTR protein function is restored, but the mechanism requires precise control of pre-mRNA splicing which increases treatment complexity

Engineering Contradiction:

ImproveCFTR protein functionVSAvoidsplicing control precision

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The antisense oligonucleotides are designed with specific sequences that target particular regions of the pre-mRNA, such as exon-intron boundaries or splice site sequences. This localized targeting ensures that splicing modifications occur only at the desired locations, enabling precise control over which exons are skipped or included while leaving other parts of the transcript unaffected

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs modified nucleotide sequences and chemical modifications to the antisense oligonucleotides that change their binding affinity and specificity parameters. By adjusting these molecular parameters, the treatment achieves precise control over splicing outcomes while maintaining ease of administration

Inventive Principle:

Principle #35Parameter changes

3Reliability

If exons with mutations are skipped to restore the open reading frame, then functional CFTR protein is produced, but the natural C-terminal portion of the protein is lost

Engineering Contradiction:

ImproveCFTR protein functionalityVSAvoidC-terminal portion of CFTR protein

Core Design Contradiction:

ReliabilityVSLoss of substance

Solution Approach 1:

The antisense oligonucleotides are designed to induce skipping of specific exons containing premature termination codons or mutation sequences. By selectively removing these problematic exons from the final transcript, the treatment extracts the harmful genetic elements while preserving the essential coding sequences needed for functional CFTR protein production

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The treatment converts the presence of mutant exons, which would normally lead to non-functional truncated proteins, into an opportunity to create optimized transcripts. By inducing skipping of specific exons, the process transforms potentially harmful genetic material into a beneficial outcome where the remaining exons combine to form a functional, albeit modified, CFTR protein with restored activity

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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

This approach effectively restores CFTR protein function in patients with CFTR mutations, particularly those with premature termination codons, offering a promising therapeutic option for improving treatment outcomes.

Implementation Method 1

compounds comprising oligonucleotides complementary to a cystic fibrosis transmembrane conductance regulator (CFTR) RNA transcript. Certain such compounds are useful for hybridizing to a CFTR transcript

Methodology Applied

Scientific EffectHybridization:

Data Source

PatentUS20210401869A1Antisense Compounds Targeting Genes Associated with Cystic Fibrosis

Publication Date: 2021.12.30 ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE

AI summary

The present disclosure relates generally to compounds comprising oligonucleotides complementary to a cystic fibrosis transmembrane conductance regulator (CFTR) RNA transcript. Certain such compounds are useful for hybridizing to a CFTR RNA transcript, including but not limited to a CFTR RNA transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing and/or expression of the CFTR transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with Cystic Fibrosis.