Modified Antisense Oligonucleotides for GAA Enzyme Activity
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Solution Overview
Problem
Current treatments for glycogen storage disease type II (GSD-II), including drug therapies, dietary manipulations, and enzyme replacement therapy, have limited success in restoring enzymatically active acid alpha-glucosidase (GAA) protein levels.
Innovation Solution
Development of modified antisense oligonucleotides that target specific regions within the GAA gene pre-mRNA, promoting the retention of exon 2 and thereby enhancing GAA enzyme activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments (enzyme replacement therapy, dietary manipulations, drug therapies) are used, then GSD-II patients receive treatment, but GAA protein levels and enzyme activity remain insufficient
Solution Approach 1:
The patent changes the molecular parameters of the treatment by using modified antisense oligonucleotides with specific chemical modifications (2'-O-methyl, 2'-O-acyl groups) and precise sequence design targeting intron 1 regions. These parameter changes enable the oligos to achieve at least 2-fold induction of GAA enzyme activity, overcoming the insufficiency of conventional treatments.
Solution Approach 2:
The patent replaces conventional mechanical/physical treatment approaches (enzyme replacement therapy involving protein delivery, dietary manipulations) with a molecular mechanism-based approach using antisense oligonucleotides that directly modulate gene expression at the RNA level, achieving more effective GAA protein restoration.
2Reliability
If fully complementary antisense oligonucleotides are used, then binding to GAA pre-mRNA is achieved, but GAA enzyme activity induction is limited
Solution Approach 1:
The patent applies local quality by designing antisense oligonucleotides with specific chemical modifications at particular locations along the sequence. The 2'-O-methyl and 2'-O-acyl modifications are placed at specific positions to enhance binding affinity and induce exon 2 inclusion, achieving at least 2-fold GAA activity induction without requiring perfect complementarity throughout the entire sequence.
Solution Approach 2:
The patent segments the antisense oligonucleotide into functional regions with specific modifications. The oligo sequence is divided into segments that target specific regions within intron 1, with different chemical modifications applied to different segments to optimize both binding and splicing modulation functions.
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 modified antisense oligonucleotides induce GAA enzyme activity at least two-fold compared to fully complementary antisense oligonucleotides, potentially offering an improved treatment for GSD-II.
Implementation Method 1
The modified antisense oligonucleotide includes a targeting sequence complementary to a target region within the pre-mRNA of the human alpha glucosidase (GAA) gene
Data Source
AI summary
The present disclosure relates to modified antisense oligonucleotides. The nucleotides described herein are of 10 to 40 nucleobases and include a targeting sequence complementary to a target region within intron 1 of a pre-mRNA of the human alpha glucosidase (GAA) gene. The target region includes at least one additional nucleobase compared to the targeting sequence, wherein the at least one additional nucleobase has no complementary nucleobase in the targeting sequence, and wherein the at least one additional nucleobase is internal to the target region.