Splice Switching Oligonucleotides for PCD Gene Correction
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Solution Overview
Problem
Current treatments for primary ciliary dyskinesia (PCD) lack effective methods for delivering nucleic acid-based therapeutics to extra-hepatic organs, particularly the lungs, where cilia defects cause respiratory issues, and there is no cure for the condition.
Innovation Solution
The use of novel splice switching oligonucleotides (SSOs), such as peptide-morpholino oligomer conjugates (PPMOs) and oligonucleotide endosomal compounds (OECs), which can correct splicing mutations in the CCDC39 gene, specifically targeting the c.1167+1262A→G mutation, to enhance pharmacological effects and improve tissue distribution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Area of stationary object
If nucleic acid-based therapeutics are administered systemically, then broad tissue distribution is achieved, but delivery to extra-hepatic organs (particularly lungs) remains insufficient
Solution Approach 1:
The patent uses peptide-morpholino oligomer conjugates (PPMOs) as intermediary delivery vehicles. The peptide component facilitates cellular uptake and tissue penetration, while the morpholino oligomer provides the therapeutic nucleic acid function. This conjugate system acts as a mediator that enables effective delivery of nucleic acid therapeutics to extra-hepatic organs, particularly the lungs, overcoming the limitation of systemic administration alone.
2Quantity of substance
If oligonucleotides are delivered to cells, then they become trapped in endosomal compartments, but this prevents access to cytosol and nucleus for pharmacological effect
Solution Approach 1:
The patent incorporates oligonucleotide endosomal compounds (OECs) that act preliminary to the main therapeutic action. These OECs are designed to preemptively disrupt endosomal compartments before the oligonucleotides become permanently trapped, creating a pathway for escape. This preliminary action prevents the harmful entrapment before it occurs, allowing the oligonucleotides to reach their intended targets in the cytosol and nucleus.
Solution Approach 2:
Oligonucleotide endosomal compounds (OECs) serve as intermediary agents that facilitate the transition of oligonucleotides from endosomal compartments to the cytosol and nucleus. These OECs mediate the escape process by interacting with both the endosomal membrane and the oligonucleotides, enabling their release and subsequent access to the cellular compartments where pharmacological effects occur.
3Reliability
If splice switching oligonucleotides are used to correct splicing mutations, then therapeutic effect is achieved, but delivery to target tissues remains a major obstacle
Solution Approach 1:
The patent employs composite material structures in the form of peptide-morpholino oligomer conjugates. This composite combines the cell-penetrating properties of peptides with the splicing-correcting functionality of morpholino oligomers. The composite structure integrates both delivery capability and therapeutic function into a single molecular entity, enabling effective splicing correction in target tissues by overcoming delivery barriers.
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
These oligonucleotides effectively correct splicing defects in PCD patient-derived airway epithelial cells, potentially delaying the onset or treating PCD by increasing the expression of wild-type CCDC39 protein, thereby addressing the limitations of existing delivery methods and providing a therapeutic approach for PCD.
Implementation Method 1
the oligonucleotide specifically hybridizes to an mRNA produced from the mutated CCDC39 gene at a site within 100 nucleotides of the mutation
Data Source
AI summary
This invention relates to the finding that novel splice switching oligonucleotides can correct splicing mutations. Moreover, the invention relates to using the novel splice switching oligonucleotides to correct the c.1167+1262A→G mutation in a pre-mRNA produced from the human CCDC39 gene and methods of using the same for treatment of primary ciliary dyskinesia (PCD) in a subject.