Antisense Oligonucleotides Modulating CFTR RNA Splicing
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Solution Overview
Problem
Current treatments for cystic fibrosis lack effective therapies to restore the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, leading to persistent lung infections and other organ dysfunctions.
Innovation Solution
Development of antisense oligonucleotides (ASOs) that specifically target and modulate the splicing of CFTR gene transcripts, inducing skipping of aberrant exons to produce functional CFTR protein by hybridizing with CFTR RNA transcripts, thereby restoring protein function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments (antibiotics, inhaled therapies) are used for cystic fibrosis, then lung infections are treated and symptoms are managed, but the underlying CFTR protein dysfunction is not restored and disease progression continues
Solution Approach 1:
The patent uses antisense oligonucleotides as intermediary molecules that bind to CFTR pre-mRNA to modulate splicing. These ASOs act as mediators between the therapeutic goal (restoring CFTR function) and the molecular target (pre-mRNA splicing machinery), enabling precise correction of splicing defects without directly interacting with the CFTR protein itself.
Solution Approach 2:
The invention applies preliminary action by correcting splicing defects at the pre-mRNA level before protein translation occurs. By modulating splicing of CFTR pre-mRNA to include exon 16 (which is normally skipped due to mutations), the therapy restores functional CFTR protein production in advance, preventing the development of cystic fibrosis symptoms rather than merely treating them after onset.
2Manufacturing precision
If antisense oligonucleotides are designed to target CFTR transcripts, then specific splicing modulation is achieved, but the complexity of identifying and targeting specific exon regions increases
Solution Approach 1:
The patent applies segmentation by dividing the CFTR pre-mRNA molecule into discrete exon and intron segments, then designing ASOs to target specific exon-intron junctions. This segmentation approach allows precise control over which exons are included or excluded in the mature mRNA, enabling targeted correction of specific splicing defects without affecting other regions of the transcript.
Solution Approach 2:
The invention implements local quality by designing ASOs with specific sequences that bind to particular regions of CFTR pre-mRNA (such as exon 16 and flanking intronic regions). Each ASO is tailored to have high affinity for its specific target sequence, ensuring that splicing modulation occurs only at the intended location without off-target effects on other CFTR exons or genes.
3Reliability
If ASOs are used to induce exon skipping or inclusion, then functional CFTR protein levels increase, but the need for precise control of splicing events increases treatment complexity
Solution Approach 1:
The patent employs self-service by designing ASOs that automatically guide the cell's native splicing machinery to produce the desired splicing outcome. The ASOs bind to specific sequences in CFTR pre-mRNA and recruit or block splicing factors, allowing the cell's own spliceosome to perform the correction without requiring external manipulation or complex delivery systems. The therapeutic effect is achieved through the ASO's ability to self-assemble with the target RNA and exploit endogenous cellular processes.
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 use of ASOs effectively increases the levels of correctly localized and functional CFTR protein at the plasma membrane, improving protein function and potentially delaying or preventing the onset of cystic fibrosis symptoms.
Implementation Method 1
compounds comprising oligonucleotides complementary to a cystic fibrosis transmembrane conductance regulator (CFTR) RNA transcript... such compounds are useful for hybridizing to a CFTR transcript
Data Source
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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 of the CFTR transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with Cystic Fibrosis.