Antisense Oligomer Splicing Modulation for GAA Protein Restoration
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Solution Overview
Problem
Current treatments for glycogen storage disease type II (GSD-II), including enzyme replacement therapy, have limited success in restoring enzymatically active acid alpha-glucosidase (GAA) protein levels, particularly in patients with the IVS1-13T>G mutation, which leads to reduced expression of exon 2-containing GAA mRNA.
Innovation Solution
The use of antisense oligomers specifically designed to hybridize with regions within the GAA gene, such as intron 1, exon 2, or intron 2, to increase the levels of exon 2-containing GAA-coding mRNA by binding to specific sequences, thereby enhancing the expression of functional GAA protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If enzyme replacement therapy is used to treat GSD-II, then some GAA protein activity is restored, but the treatment has limited success in restoring enzymatically active GAA protein levels
Solution Approach 1:
The patent uses antisense oligomers as intermediary molecules that bind to specific regions of pre-mRNA (intron 1, exon 2, or intron 2) to modulate splicing. This intermediary approach allows the treatment to specifically increase exon 2-containing GAA mRNA levels, thereby restoring enzymatically active GAA protein levels more effectively than non-specific enzyme replacement therapy
Solution Approach 2:
The patent changes the molecular parameter of pre-mRNA splicing by introducing antisense oligomers that bind to specific sequences. This parameter change in the splicing process leads to increased levels of exon 2-containing GAA mRNA, which directly addresses the limitation of enzyme replacement therapy in restoring sufficient enzymatically active protein levels
2Quantity of substance
If the IVS1-13T>G mutation is present, then exon 2 is lost from GAA mRNA, but this leads to reduced expression of exon 2-containing GAA mRNA and insufficient GAA protein
Solution Approach 1:
The patent converts the harmful effect of the IVS1-13T>G mutation (which causes exon 2 loss) into a beneficial outcome by using antisense oligomers to target specific regions of the pre-mRNA. The antisense oligomers bind to intron 1, exon 2, or intron 2 to promote exon 2 inclusion, thereby converting the mutation's harmful splicing effect into a therapeutic benefit that restores exon 2-containing GAA mRNA expression
Solution Approach 2:
The antisense oligomers serve as intermediary molecules that bridge the gap created by the IVS1-13T>G mutation. By binding to specific sequences in the pre-mRNA, these intermediaries redirect the splicing process to include exon 2, thereby restoring the quantity and quality of functional GAA protein despite the presence of the mutation
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 increase the levels of exon 2-containing GAA mRNA and functional GAA protein in cells, potentially reducing glycogen accumulation and improving clinical outcomes for GSD-II patients, including those with the IVS1-13T>G mutation.
Implementation Method 1
contacting the cell with an antisense oligomer of sufficient length and complementarity to specifically hybridize to a region within the pre-mRNA of the GAA gene
Data Source
AI summary
The present disclosure relates to antisense oligomers and related compositions and methods for inducing exon inclusion as a treatment for glycogen storage disease type II (GSD-II) (also known as Pompe disease, glycogenosis II, acid maltase deficiency (AMD), acid alpha-glucosidase deficiency, and lysosomal alpha-glucosidase deficiency), and more specifically relates to inducing inclusion of exon 2 and thereby restoring levels of enzymatically active acid alpha-glucosidase (GAA) protein encoded by the GAA gene.