Antisense Oligonucleotides Downregulate Glycogen Synthase for Pompe Disease
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Solution Overview
Problem
Current treatments for Pompe disease, such as enzyme replacement therapy, are not entirely effective, and there is a need for alternative therapies that can reduce glycogen accumulation in skeletal and cardiac muscles, as glycogen synthase activity is elevated in Pompe mice, interfering with normal regulation and enzyme function.
Innovation Solution
Administration of antisense oligonucleotides, specifically phosphorodiamidate morpholino oligomers (PMOs) or PMO conjugated with cell-penetrating peptides, that target and downregulate glycogen synthase 1 mRNA by inducing exon skipping or translational inhibition, reducing glycogen synthase enzyme activity and accumulation in muscles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If enzyme replacement therapy is used to treat Pompe disease, then glycogen accumulation is reduced to some extent, but the treatment is not entirely effective and additional therapies are needed
Solution Approach 1:
The patent divides the treatment approach into two complementary strategies: enzyme replacement therapy to clear existing glycogen and substrate reduction therapy using antisense oligonucleotides to prevent new glycogen synthesis. This segmentation of therapeutic mechanisms addresses the limitation of using either approach alone.
Solution Approach 2:
The patent introduces antisense oligonucleotides as an intermediary agent that binds to glycogen synthase mRNA to prevent protein synthesis. This intermediary mechanism provides an alternative pathway to reduce glycogen accumulation that does not depend on enzyme replacement alone.
2Object-generated harmful factors
If glycogen synthase activity is inhibited to reduce glycogen accumulation, then glycogen buildup is reduced, but enzyme activity regulation is interfered with
Solution Approach 1:
The patent uses antisense oligonucleotides as temporary, disposable agents that bind to mRNA to prevent glycogen synthase synthesis. These oligonucleotides are administered periodically rather than requiring permanent modification of enzyme regulation systems, allowing flexible control over glycogen synthesis inhibition.
3Object-generated harmful factors
If substrate reduction therapy is used to inhibit glycogen synthase, then glycogen accumulation is reduced, but the dose required may have off-target effects
Solution Approach 1:
The patent employs antisense oligonucleotides that are designed to bind specifically to glycogen synthase mRNA sequences, providing localized and specific inhibition of glycogen synthase protein synthesis. This sequence-specific binding ensures that only the target enzyme is affected without interfering with other cellular processes or enzymes.
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 approach effectively reduces glycogen synthase 1 mRNA and protein levels in skeletal and cardiac muscles, leading to decreased glycogen accumulation, alleviating symptoms associated with glycogen buildup, while being specific to muscle isoforms and avoiding liver glycogen synthase, thus maintaining systemic glucose mobilization.
Implementation Method 1
the hybridization of the antisense oligonucleotide to the nucleic acid sequence encoding for glycogen synthase induces exon skipping
Data Source
AI summary
The present disclosure relates to antisense oligonucleotides (AONs) for modulating the expression of glycogen synthase. AONs of the present disclosure may be useful in treating diseases associated with the modulation of the expression of the enzyme glycogen synthase, such as Pompe disease. Also provided by the present disclosure are compositions comprising AONs, as well as methods of down regulating mRNA coding for glycogen synthase, methods for reducing glycogen synthase in skeletal and cardiac muscle, and methods for treating Pompe disease.