Antisense Oligonucleotides for Shank3 Expression in Phelan-McDermid Syndrome
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Solution Overview
Problem
Current therapies for Shank3 deficiency diseases, such as Phelan-McDermid syndrome, are primarily symptomatic and do not effectively address the underlying genetic cause, with a need for treatments that can improve Shank3 expression levels in affected cells.
Innovation Solution
Development of oligonucleotides specifically binding to the Shank3 gene sequence, which can increase Shank3 protein levels in cells by preventing mRNA degradation, thereby addressing the genetic deficiency and improving molecular and behavioral properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If symptomatic therapies (insulin, Lithium, risperidone, IGF-I) are administered, then single symptoms improve, but the underlying genetic cause of Shank3 deficiency remains unaddressed
Solution Approach 1:
The invention extracts and targets the specific molecular mechanism causing the disease (Shank3 gene expression deficiency) rather than treating downstream symptoms. The antisense oligonucleotide specifically binds to the Shank3 pre-mRNA to modulate splicing and increase functional Shank3 protein expression, directly addressing the genetic cause while the symptomatic treatments address only downstream effects
Solution Approach 2:
Instead of treating symptoms by suppressing neuronal activity or behavior (the conventional symptomatic approach), the invention inverts the strategy by enhancing the expression of the deficient Shank3 protein itself. This upstream intervention aims to restore normal synaptic function rather than merely controlling behavioral outputs
2Productivity
If antisense oligonucleotides are designed to bind Shank3 pre-mRNA, then Shank3 protein expression increases, but specificity to the target sequence must be maintained
Solution Approach 1:
The invention applies local quality by designing the oligonucleotide to bind to a specific local region (nucleotides 100-300) of the Shank3 pre-mRNA rather than the entire transcript. This localized binding approach ensures high specificity to the target sequence while effectively modulating splicing at the critical exon inclusion site
Solution Approach 2:
The invention utilizes parameter changes by optimizing the oligonucleotide sequence parameters (nucleotide composition, length, binding affinity) to achieve maximum specificity and effectiveness. The sequence is designed to complementarily bind to the target pre-mRNA region with high affinity while maintaining selectivity against off-target sequences
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 oligonucleotides effectively increase Shank3 protein expression, potentially leading to improved symptoms and treatment outcomes for Shank3 deficiency diseases, including Phelan-McDermid syndrome, by enhancing protein production and stabilizing synapses.
Implementation Method 1
antisense oligonucleotides specifically binding to a polynucleotide comprising the nucleic acid sequence set out in SEQ ID NO: 1
Data Source
AI summary
The present invention relates to an oligonucleotide specifically binding to a polynucleotide comprising the nucleic acid sequence of SEQ ID NO:1. The present invention also relates to said oligonucleotide for use in medicine and for use in treatment and/or prevention of Shank3 deficiency, preferably for use in treatment and/or prevention of Phelan-McDermid syndrome. The present invention also relates to expression constructs, host cells, and methods related thereto.