CFTR Splicing Modulation to Suppress Intron 22 Cryptic Exon
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Solution Overview
Problem
There is a need for novel therapeutic approaches to manage cystic fibrosis (CF) by restoring the function of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, particularly for mutations that cause aberrant splicing and reduced chloride conductance, such as the 3849+10Kb C-to-T mutation leading to intron 22 cryptic exon inclusion.
Innovation Solution
Development of synthetic oligonucleotides that bind to CFTR pre-mRNA to modulate splicing, suppressing the inclusion of intron 22 cryptic exon and enhancing the production of functional CFTR protein by increasing the percentage of correctly spliced mRNA and decreasing aberrantly spliced mRNA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the 3849+10Kb C-to-T mutation is present in the CFTR gene, then the pre-mRNA undergoes aberrant splicing leading to inclusion of intron 22 cryptic exon, but this results in production of non-functional CFTR protein with reduced chloride conductance
Solution Approach 1:
The patent uses antisense oligonucleotides as intermediary molecules that bind to the mutant CFTR pre-mRNA at the 3849+10Kb mutation site. These oligonucleotides act as mediators that block the aberrant splicing mechanism, preventing the cryptic exon inclusion by physically occupying the mutant site and redirecting the splicing machinery to use correct splice sites, thereby restoring production of functional CFTR protein
Solution Approach 2:
The patent applies parameter changes by modifying the splicing parameters through oligonucleotide binding. By introducing exogenous oligonucleotides that bind to specific sequences, the splicing parameters (splice site selection, exon inclusion/exclusion) are altered from the aberrant pattern to a corrected pattern, increasing the percentage of correctly spliced mRNA and restoring CFTR function
2Reliability
If antisense oligonucleotides are administered to suppress cryptic exon inclusion, then the percentage of correctly spliced CFTR mRNA increases, but the treatment complexity and cost increase
Solution Approach 1:
The patent employs relatively simple and cost-effective antisense oligonucleotide molecules rather than complex gene editing systems or protein-based therapies. These oligonucleotides are synthetic, can be produced through standard chemical synthesis methods, and act as disposable therapeutic agents that bind to the target pre-mRNA and are subsequently degraded, providing a simpler and more affordable treatment approach compared to alternative therapies
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 oligonucleotides effectively increase the percentage of correctly spliced CFTR mRNA by at least 10% and decrease aberrantly spliced mRNA by at least 20%, potentially improving clinical parameters of cystic fibrosis, including lung function and reducing pulmonary exacerbations.
Implementation Method 1
synthetic oligonucleotides that bind to CFTR pre-mRNA to modulate splicing
Data Source
AI summary
The present invention provides oligonucleotides capable of binding to and modulating the splicing of the pre-mRNA of the CFTR gene, including compositions comprising the oligonucleotides, and uses thereof, such as for suppressing the inclusion of a cryptic exon between exon 22 and 23 as a result of the mutation 3849+10Kb C-to-T, optionally in combination with additional CF therapeutics.