Abasic Antisense Oligomers for GAA Splicing Modulation
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Solution Overview
Problem
Current treatments for glycogen storage disease type II (GSD-II), also known as Pompe disease, lack effective methods to restore enzymatically active acid alpha-glucosidase (GAA) protein levels, as existing therapies like enzyme replacement therapy have limitations and antisense technology requires improved oligonucleotides for enhanced treatment outcomes.
Innovation Solution
Development of antisense oligomers that are 18-40 subunits in length, comprising a targeting sequence complementary to a target region within intron 1 of the human GAA gene, specifically designed to induce exon inclusion and restore GAA enzyme activity by promoting the retention of exon 2 in GAA mRNA, using phosphorodiamidate morpholino oligomers or peptide-conjugated variants.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides are designed to target intron 1 to induce exon 2 inclusion, then GAA enzyme activity is restored, but the precision of splicing modulation is insufficient with conventional oligonucleotides
Solution Approach 1:
The patent introduces abasic subunits at specific positions within the antisense oligonucleotide sequence to create localized modifications that enhance binding precision to intron 1. These abasic subunits are strategically placed to improve the oligonucleotide's ability to modulate splicing at the exact target site, thereby increasing splicing modulation precision while maintaining GAA enzyme activity restoration.
Solution Approach 2:
The patent modifies the chemical structure of the oligonucleotide by incorporating abasic subunits, which change the physical and chemical parameters of the molecule. This structural parameter change enhances the binding affinity and specificity of the oligonucleotide to its target sequence in intron 1, improving both the reliability of GAA enzyme activity restoration and the precision of splicing modulation.
2Reliability
If enzyme replacement therapy is used to treat GSD-II, then GAA enzyme activity is provided externally, but the underlying genetic defect is not corrected and treatment limitations persist
Solution Approach 1:
The patent employs antisense oligonucleotides to act in advance on the pre-mRNA splicing process, preventing the formation of defective mRNA transcripts before they can be translated. This preliminary action corrects the splicing defect at the RNA level, thereby restoring endogenous GAA enzyme production and addressing the underlying genetic defect rather than merely providing external enzyme replacement.
Solution Approach 2:
The antisense oligonucleotide acts as an intermediary molecule that bridges the gap between the genetic defect and functional enzyme production. By binding to specific sequences in intron 1, the oligonucleotide mediates the correction of splicing errors, enabling the cell's own machinery to produce functional GAA enzyme and thereby overcoming the limitations of direct enzyme replacement therapy.
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 antisense oligomers effectively enhance GAA enzyme activity and mRNA levels, offering a potential therapeutic approach for Pompe disease by specifically targeting and modifying the GAA gene expression, potentially improving treatment outcomes for GSD-II patients.
Implementation Method 1
comprising a targeting sequence complementary to a target region within intron 1 (SEQ ID NO: 1) of a pre-mRNA of human acid alpha-glucosidase (GAA) gene
Data Source
AI summary
Provided herein are oligonucleotides, peptide-oligonucleotide-conjugates, and a targeting sequence complementary to a target region within intron 1 of a pre-mRNA of human acid alpha-glucosidase (GAA) gene having at least one purine and pyrimidine-free abasic subunit. Also provided herein are methods of treating a muscle disease, a viral infection, or a bacterial infection in a subject in need thereof, comprising administering to the subject oligonucleotides, peptides, and peptide-oligonucleotide-conjugates described herein.