Antisense Oligonucleotides for CFTR Splicing Correction

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Solution Overview

Problem

Current treatments for Cystic Fibrosis (CF) are inadequate in addressing the splicing mutation 3849+10 kb C-to-T, which leads to the inclusion of a cryptic exon in the CFTR mRNA, resulting in insufficient CFTR function and severe respiratory complications.

Innovation Solution

Administration of a pharmaceutical composition comprising synthetic oligonucleotides complementary to the 3849+10 Kb C-to-T mutation in the CFTR gene, combined with CFTR modifiers such as elexacaftor, tezacaftor, and ivacaftor, to suppress the inclusion of intron 22 cryptic exon and restore CFTR function.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional CFTR treatments are used, then general CF symptom management is achieved, but splicing mutation 3849+10 kb C-to-T is not addressed, resulting in persistent cryptic exon inclusion

Engineering Contradiction:

ImproveCFTR function restorationVSAvoidMutation-specific treatment coverage

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent introduces antisense oligonucleotides as intermediary molecules that specifically bind to the mutated CFTR pre-mRNA at the 3849+10 kb mutation site. These oligonucleotides act as mediators between the mutation and the splicing machinery, blocking the cryptic exon inclusion by masking the splice site. This resolves the contradiction by providing mutation-specific intervention while maintaining compatibility with general CFTR treatment approaches.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The treatment applies local quality modification by targeting only the specific 3849+10 kb mutation site with antisense oligonucleotides, rather than attempting to correct all CFTR mutations uniformly. The oligonucleotides are designed with sequences complementary to the specific mutated region, providing localized correction of the splicing defect while leaving other CFTR functions intact. This enables precise adaptation to the specific mutation type.

Inventive Principle:

Principle #3Local quality

2Manufacturing precision

If antisense oligonucleotides are administered to suppress cryptic exon inclusion, then splicing accuracy is improved, but treatment complexity increases due to combination therapy requirements

Engineering Contradiction:

ImprovemRNA splicing accuracyVSAvoidTreatment regimen complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent merges two treatment modalities into a single combination therapy: antisense oligonucleotides for splicing correction and CFTR modulators (correctors/potentiators) for protein function enhancement. The oligonucleotides are administered to suppress cryptic exon inclusion at the mRNA level, while CFTR modulators are co-administered to improve the function of the corrected CFTR protein. This combination approach achieves both splicing accuracy and functional restoration, with the added benefit that the two mechanisms work synergistically to address both the genetic defect and the resulting protein dysfunction.

Inventive Principle:

Principle #5Merging (Combining)

3Reliability

If combination therapy with multiple CFTR modifiers is used, then CFTR function is restored to near-normal levels, but treatment cost and administration burden increase

Engineering Contradiction:

ImproveCFTR function restorationVSAvoidTreatment administration simplicity

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent employs partial action by selecting specific CFTR modulators based on the patient's genotype and disease severity. Not all patients require the full combination of correctors and potentiators; rather, the treatment is tailored to provide sufficient CFTR function restoration for each individual. The antisense oligonucleotides provide the foundational splicing correction, and CFTR modulators are added in varying combinations and doses to achieve near-normal function without unnecessary complexity. This personalized approach balances treatment efficacy with administrative feasibility.

Inventive Principle:

Principle #16Partial or excessive action

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 approach significantly increases the percentage of correctly spliced CFTR mRNA and decreases aberrantly spliced mRNA, effectively restoring CFTR function to near-normal levels, as demonstrated by improved lung function and reduced pulmonary exacerbations in patients.

Implementation Method 1

ASOs are short synthetic molecules which can anneal to motifs predicted to be involved in the pre-mRNA splicing. ASO binding masks the targeted region and promote normal splicing.

Methodology Applied

Scientific EffectAnnealing: Annealing

Data Source

PatentUS20220220486A1Combination treatments for cystic fibrosis characterized by a 3849 + 10kb c-to-t CFTR mutation

Publication Date: 2022.07.14 YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY OF JERUSALEM LTD

AI summary

The present invention provides methods for treating Cystic Fibrosis (CF) and methods for suppressing the inclusion of a cryptic exon between exon 22 and 23 as a result of the mutation 3849+10 Kb C-to-T comprising the step of administering a pharmaceutical composition comprising synthetic oligonucleotides complementary to a region of the CFTR comprising the 3849+10 Kb C-to-T mutation oligonucleotides and a composition comprising one or more CFTR modifiers.