Oligonucleotides for CFTR Splicing Correction in Cystic Fibrosis
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for cystic fibrosis, particularly for patients with the p.Phe508del mutation, are inadequate in correcting CFTR protein function, leading to persistent pulmonary damage and high treatment burdens, with existing therapies failing to effectively address the underlying molecular mechanisms of the disease.
Innovation Solution
Development of miRNA binding-blocker oligonucleotides and splicing-blocker oligonucleotides that target specific miRNAs and splice sites to prevent binding, thereby increasing CFTR transcript and protein levels, and correcting aberrant splicing, respectively, to restore functional CFTR channel activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing CFTR potentiators and correctors are used, then treatment of certain CF mutations is improved, but they fail to address the most common p.Phe508del mutation and do not correct underlying splicing defects
Solution Approach 1:
The invention segments the therapeutic approach by developing separate oligonucleotide agents that target specific splicing defects and mutation types. Different oligonucleotide sequences are designed to address different CFTR mutations, including p.Phe508del, allowing tailored treatment for specific genetic variants rather than relying on a single broad-acting drug
Solution Approach 2:
The invention uses oligonucleotides as intermediary molecules that bind to specific RNA sequences to modulate splicing and restore CFTR function. These oligonucleotide intermediaries act as bridges between the genetic defect and functional correction, enabling precise intervention in the splicing process for mutations that respond to splicing modulation
2Ease of operation
If conventional therapies are administered, then symptomatic management is improved, but the underlying molecular mechanisms remain uncorrected leading to progressive pulmonary damage
Solution Approach 1:
The invention applies preliminary action by correcting the underlying splicing defects and CFTR protein production issues before they lead to irreversible pulmonary damage. By addressing the root molecular cause through oligonucleotide-mediated splicing correction, the therapy prevents disease progression rather than merely managing symptoms after damage occurs
Solution Approach 2:
The invention extracts and addresses the specific molecular defect (aberrant splicing) from the complex disease phenotype. By isolating and correcting the splicing error as a distinct target, the therapy separates the treatable molecular cause from the downstream symptomatic manifestations, allowing direct intervention at the genetic level
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 demonstrate a significant increase in CFTR transcript and protein levels, enhancing chloride transport and potentially improving the clinical phenotype of cystic fibrosis patients by stabilizing CFTR transcripts and increasing functional protein production.
Implementation Method 1
miRNA binding-blocker oligonucleotides comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3
Implementation Method 2
splicing-blocker oligonucleotides that target specific miRNAs and splice sites to prevent binding, thereby increasing CFTR transcript and protein levels, and correcting aberrant splicing
Data Source
Figure 1A
Figure 1B
Figure 1C
AI summary
The present invention relates to a method and compositions for the treatment of cystic fibrosis.