Antisense Oligomers Restore ATM Splicing
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Solution Overview
Problem
Ataxia Telangiectasia (A-T) is an incurable autosomal recessive disease caused by mutations in the ATM gene, leading to neurodegeneration, immune deficiency, and aberrant splicing, with current treatments lacking effective solutions to restore wild-type splicing and manage the disease progression.
Innovation Solution
The use of antisense nucleobase oligomers, specifically designed to target and restore wild-type splicing of the ATM gene by hybridizing with mutated sequences, including phosphorothioate and locked nucleic acid modifications, to correct aberrant splicing and improve ATM gene function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for Ataxia Telangiectasia, then disease management is attempted, but wild-type splicing cannot be restored and disease progression continues
Solution Approach 1:
An antisense oligonucleotide acts as an intermediary molecule that binds to the mutated ATM pre-mRNA sequence, blocking the aberrant splicing process and redirecting it toward wild-type splicing, thereby restoring functional ATM protein production
Solution Approach 2:
The invention changes the splicing parameters by introducing an antisense oligonucleotide that alters the splicing pattern of the ATM gene, shifting from aberrant splicing to wild-type splicing, thereby changing the outcome of gene expression
2Ease of operation
If the ATM gene mutation is present, then Ataxia Telangiectasia disease occurs, but current treatments lack effective solutions
Solution Approach 1:
The invention extracts the harmful effect of the ATM gene mutation by using an antisense oligonucleotide to specifically target and correct the aberrant splicing caused by the mutation, separating the pathological effect from the genetic cause
Solution Approach 2:
The antisense oligonucleotide is administered preliminarily to block aberrant splicing before it can produce harmful effects, preventing the formation of defective ATM protein and potentially preventing disease progression
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
These antisense oligomers effectively restore wild-type splicing in cells with ATM gene mutations, enhancing ATM kinase activity and improving cellular function, potentially leading to therapeutic benefits for A-T patients by promoting correct splicing and reducing disease symptoms.
Implementation Method 1
antisense nucleobase oligomers, specifically designed to target and restore wild-type splicing of the ATM gene by hybridizing with mutated sequences
Data Source
AI summary
Provided herein are antisense oligonucleotides and prophylactic and therapeutic methods featuring such oligonucleotides. These oligonucleotides and methods are useful for treating or preventing ataxia telangiectasia in a subject. Specifically, the disclosure provides antisense nucleobase oligomers each comprising (8-40) nucleobases, wherein at least 90% of said nucleobases or more than (8) consecutive nucleobases of the oligomer are complementary to a nucleic acid sequence in an Ataxia-Telangiectasia Mutated (ATM) allele comprising a mutation associated with aberrant splicing.