Antisense Oligonucleotide Splicing Correction for Pompe Disease
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Solution Overview
Problem
Current treatments for Pompe disease, such as enzyme replacement therapy (ERT) and antisense oligonucleotides, face challenges in effectively targeting and increasing GAA enzyme activity, particularly with the IVS1 mutation, which requires exon inclusion rather than skipping, and are limited by antibody responses, high production costs, and short enzyme half-life.
Innovation Solution
A combination therapy using antisense oligomeric compounds (AONs) that block natural cryptic splice sites in the GAA gene to restore wild-type splicing, paired with ERT, to enhance GAA enzyme activity beyond levels achievable with standard ERT dosages.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If enzyme replacement therapy (ERT) is used to increase intracellular GAA enzyme levels, then glycogen accumulation is reduced, but the treatment is limited by short enzyme half-life, antibody responses, and high production costs
Solution Approach 1:
The patent applies preliminary action by using antisense oligonucleotides to pre-modify the splicing of GAA pre-mRNA before enzyme administration, ensuring that the correct wild-type splicing pattern is established in advance. This preliminary splicing correction creates optimal conditions for subsequent ERT to achieve higher and more sustained intracellular enzyme levels by preventing premature degradation and antibody formation.
Solution Approach 2:
The patent changes the splicing parameter of GAA pre-mRNA from aberrant patterns to wild-type patterns through antisense oligonucleotide intervention. This parameter change in splicing efficiency and accuracy directly improves the stability and half-life of the resulting enzyme protein, allowing ERT to maintain therapeutic enzyme levels for longer durations.
2Quantity of substance
If standard ERT dosages are administered, then some glycogen accumulation is reduced, but enzyme activity cannot exceed levels achievable with current dosing regimens
Solution Approach 1:
The patent merges two therapeutic approaches: antisense oligonucleotide therapy that corrects GAA pre-mRNA splicing at the molecular level, and enzyme replacement therapy that supplies functional GAA enzyme. This combination creates a synergistic effect where splicing correction enhances enzyme stability and activity, allowing treatment efficacy to exceed what either approach could achieve alone, even with reduced ERT dosages.
3Manufacturing precision
If antisense oligonucleotides are used to modulate splicing, then aberrant splicing is corrected, but the approach is limited by difficulty in targeting specific splice sites and potential off-site effects
Solution Approach 1:
The patent uses antisense oligonucleotides as intermediary molecules that specifically bind to target sequences in GAA pre-mRNA to redirect splicing to the wild-type pattern. These oligonucleotides act as mediators between the aberrant splicing process and the desired correct splicing outcome, providing precise control over splice site selection while minimizing off-target effects through sequence-specific binding.
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
This approach significantly increases intracellular GAA enzyme levels, overcoming limitations of ERT by promoting exon inclusion and achieving enzyme activity comparable to or exceeding that of healthy individuals, with potential for reduced dosages and improved treatment efficacy.
Implementation Method 1
A combination therapy using antisense oligomeric compounds (AONs) that block natural cryptic splice sites in the GAA gene to restore wild-type splicing
Implementation Method 2
Enzyme replacement therapy (ERT) has been developed for Pompe disease, in which recombinant human GAA protein is administered intravenously every two weeks. This treatment is aimed to increase the intracellular level of n-glucosidase activity in affected cells and tissues and thereby reduce or prevent glycogen accumulation
Data Source
AI summary
The invention relates to method for repairing aberrant; splicing, wherein such aberrant: splicing is caused by the presence of a natural pseudo exon, comprising blocking of either the natural cryptic 3′ splice site or the natural cryptic 5′ splice site of said natural pseudo exon with an antisense oligomeric compound (AON). Further, the invention comprises an antisense oligomeric compound targeting SEQ ID NO: 1 or SEQ ID NO: 171, preferably selected from the sequences of SEQ ID NO: 267-2040, sequences that are complementary to said sequences or sequences that have an identity of 80% with said sequences or the complementary sequences. The invention further envisages the use of two antisense oligomeric compounds, a first AON targeting SEQ ID NO: 1 and a second targeting AON or SEQ ID NO: 171. These AONs are specifically for use in the treatment of Pompe disease. It is an aspect of the invention that antisense therapy using the above AONs or combinations thereof is used in combination with ERT.