ATM Splicing Modulation Using NSE Switch Oligonucleotides
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Solution Overview
Problem
Existing technologies struggle to effectively modulate gene expression for deregulated protein levels, particularly in conditions associated with functional ATM protein deficiency, which can lead to diseases such as ataxia-telangiectasia, immune deficiency, and cancer, due to the complex interactions between intronic and exonic variants and spliceosomal components.
Innovation Solution
The use of NSE repressor and activator agents, such as splice-switching oligonucleotides (SSOs), to target specific splicing regulatory motifs in the ATM gene, including cryptic exons and pseudoexons, to modulate the inclusion of NSE in mature RNA transcripts, thereby regulating ATM protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides target splicing regions to restore protein expression, then functional ATM protein levels increase, but the complexity of modulating gene expression increases due to intronic and exonic variant interactions
Solution Approach 1:
The invention divides the complex splicing regulation problem into targeted segments by designing specific oligonucleotide agents that bind to particular splicing regulatory motifs (such as cryptic exons or pseudoexons) within the ATM gene. This segmentation allows precise modulation of specific splicing events without needing to control all splicing variants simultaneously, thereby reducing the effective complexity while restoring functional protein expression.
Solution Approach 2:
The patent employs oligonucleotide agents as intermediary molecules that mediate between the splicing machinery and the ATM pre-mRNA. These intermediaries bind to specific splicing regulatory motifs and modulate splice site selection, acting as controllable mediators that can restore functional ATM protein expression without directly manipulating the complex spliceosomal components themselves.
2Object-affected harmful factors
If NSE inclusion is increased to reduce functional ATM protein, then cancer cell susceptibility to DNA damaging therapy increases, but therapeutic precision decreases due to population-dependent splicing regulation
Solution Approach 1:
The invention applies local quality by designing oligonucleotide agents with sequences specifically tailored to bind splicing regulatory motifs that are locally present in cancer cell populations with deregulated ATM expression. The agents are customized to target specific cryptic exons or pseudoexons that are activated in particular cancer contexts, thereby achieving precise therapeutic effects tailored to the local splicing landscape of the cancer cells while increasing their susceptibility to DNA damaging therapy.
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 allows for precise modulation of ATM protein levels, enhancing therapeutic efficacy in conditions like ataxia-telangiectasia and cancer by increasing or decreasing functional ATM protein expression, thus addressing the deficiencies and associated conditions.
Implementation Method 1
splice-switching oligonucleotides (SSOs), to target specific splicing regulatory motifs in the ATM gene
Data Source
Figure 1A~1C
Figure 2A~2C
Figure 2D~2I
AI summary
Disclosed herein include compositions and methods of modulating protein expression that utilizes an activator or a repressor of a non-sense mediated RNA decay switch exon (NSE).In some embodiments, also included herein are compositions and methods of modulating protein expression that uses an agent that targets a transposed element.