Modified Oligonucleotides Targeting SCN2A uORFs
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Solution Overview
Problem
Current methods are ineffective in treating neurological and psychiatric disorders associated with decreased expression or activity of the SCN2A gene, such as developmental epileptic encephalopathies, autism, and schizophrenia, as there is a lack of effective treatments available.
Innovation Solution
Development of modified oligonucleotides that are complementary to specific regions of the SCN2A gene mRNA, designed to increase its expression by binding to upstream open reading frames without triggering mRNA degradation, thereby enhancing the translation of the SCN2A protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If modified oligonucleotides are designed to bind to upstream open reading frames of SCN2A mRNA, then SCN2A expression is increased, but there is a risk of triggering mRNA degradation through RNase H or RISC pathways
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of the oligonucleotide backbone and sugar moieties. Specifically, the use of phosphorodiamidate morpholino (PMO) internucleoside linkages and 2′-O-methoxyethyl (2MOE) modified sugars changes the physical and chemical parameters of the oligonucleotide, making it resistant to RNase H degradation while maintaining binding affinity to the target mRNA sequence
Solution Approach 2:
The modified oligonucleotide acts as an intermediary that binds to the upstream open reading frame of SCN2A mRNA without triggering the RNA-induced silencing complex (RISC) pathway. The unique chemical structure of PMO and 2MOE modifications allows the oligonucleotide to mediate protein translation enhancement without activating harmful degradation pathways
2Quantity of substance
If conventional oligonucleotides are used to target SCN2A mRNA, then mRNA degradation occurs through RNase H activation, but this does not increase SCN2A expression
Solution Approach 1:
The patent fundamentally changes the chemical parameters of the oligonucleotide by replacing the standard phosphodiester backbone with phosphorodiamidate morpholino linkages and modifying the sugar ring structure with 2′-O-methoxyethyl groups. These parameter changes render the oligonucleotide resistant to RNase H activation while preserving its ability to bind target mRNA and enhance translation
Solution Approach 2:
The patent converts the potential harm of oligonucleotide-mRNA binding (which could trigger degradation) into a beneficial effect by designing modified oligonucleotides that specifically avoid activating RNase H and RISC pathways. The modified structure allows binding without the harmful consequences, thus converting a potentially harmful interaction into a therapeutic benefit
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 oligonucleotides effectively increase SCN2A expression, providing a therapeutic benefit for treating neurological and psychiatric disorders by targeting and altering the translation of the SCN2A gene, potentially reducing symptoms associated with these conditions.
Implementation Method 1
has a nucleobase sequence with a portion of at least 10 contiguous nucleobases complementary to an equal length portion of a target region of an mRNA transcript upstream of a primary open reading frame (pORF) of a human SCN2A gene
Data Source
AI summary
Described herein are compositions and methods that are used to increase the expression of SCN2A, which may be used to treat neurological or psychiatric disorders. Antisense oligonucleotides that target upstream open reading frames (uORFs) may be administered to prevent translation initiation from a uORF to increase expression from a primary ORF (pORF), thus increasing the levels of SCN2A protein.