Antisense Oligonucleotides for SYNGAP1 Haploinsufficiency Expression Rescue
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Solution Overview
Problem
There are no disease-specific or disease-modifying treatments for SYNGAP1-related neurodevelopmental disorders, which are characterized by haploinsufficiency leading to conditions such as intellectual disability, epilepsy, and autism spectrum disorder, caused by mutations in the SYNGAP1 gene.
Innovation Solution
The use of antisense oligonucleotides (ASOs) to upregulate SynGAP protein expression by blocking miRNA interference, mitigating negative regulatory effects of the 5' UTR, and depleting long non-coding RNAs (lncRNAs) that interfere with SYNGAP1 expression, thereby promoting the production of functional SynGAP protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If antisense oligonucleotides are used to block miRNA interference and upregulate SynGAP protein expression, then protein production increases, but the complexity of the treatment approach increases
Solution Approach 1:
The patent employs antisense oligonucleotides as intermediary molecules that bind to miRNAs to prevent them from interfering with SYNGAP mRNA translation. This mediator approach allows indirect upregulation of SynGAP protein without directly modifying the gene or using complex gene therapy vectors, thus improving protein production while maintaining relatively manageable treatment complexity.
2Reliability
If multiple mechanisms are targeted simultaneously (miRNA blocking, 5' UTR mitigation, lncRNA depletion), then treatment effectiveness increases, but the manufacturing and delivery complexity increases
Solution Approach 1:
The patent designs antisense oligonucleotides with multi-functional capabilities: some ASOs block miRNA binding sites on SYNGAP mRNA, others target negative regulatory elements in the 5' UTR, and additional ASOs deplete antisense lncRNAs. This multi-functional approach allows a single class of molecule (ASOs) to address multiple pathological mechanisms simultaneously, improving treatment effectiveness while avoiding the need for entirely separate therapeutic agents for each mechanism.
3Quantity of substance
If ASOs are designed to bind to multiple target sites on SYNGAP mRNA and related RNAs, then protein expression is upregulated more effectively, but the precision of target delivery decreases
Solution Approach 1:
The patent divides the therapeutic approach into multiple segmented ASO molecules, each targeting specific sites: miRNA binding sites in the 3' UTR, regulatory elements in the 5' UTR, and antisense lncRNA sequences. This segmentation allows each ASO to have a focused, precise target while the collective action of multiple ASOs achieves comprehensive upregulation of SynGAP expression, balancing individual target precision with overall therapeutic effectiveness.
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 ASOs increase SynGAP protein production, leading to a healthy phenotype despite the haploinsufficient genotype, effectively treating or preventing the development of SYNGAP1-related symptoms and conditions.
Implementation Method 1
The invention provides compositions that include synthetic antisense oligonucleotides (ASOs) that prevent miRNAs from interfering with production of the SynGAP protein
Implementation Method 2
The invention provides antisense oligonucleotide (ASO) gapmers that hybridize to SYNGAP1-AS and promote RNaseH-mediated depletion of SYNGAP1-AS
Data Source
AI summary
The invention relates to therapeutic compositions for disorders associated with haploinsufficiency. The invention provides antisense oligonucleotides useful for treating neurodevelopmental disorders associated with mutations in the SYNGAP gene. The invention provides compositions that include synthetic antisense oligonucleotides (ASOs) that promote expression of the SynGAP protein by one or any combination of (i) preventing one or more miRNAs from interfering with production of the SynGAP protein; (ii) binding to 5′-UTR of the SYNGAP1 transcript and augmenting translation of the Syngap protein; and (iii) promoting RNAseH cleavage of antisense long non-coding RNAs that are anticorrelated with SYNGAP expression. When the composition is delivered to a patient with SYNGAP haploinsufficiency, the ASOs promote expression of the SynGAP protein.