Antisense Oligonucleotide Targeting ATN1 mRNA for DRPLA
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Solution Overview
Problem
Current treatments for dentatorubral-pallidoluysian atrophy (DRPLA) are symptomatic and do not effectively address the molecular mechanism underlying the disease, resulting in low treatment satisfaction.
Innovation Solution
Development of an antisense oligonucleotide targeting the ATN1 mRNA or pre-mRNA, specifically designed to be complementary to nucleic acid sequences within certain regions of the ATN1 gene, with the goal of reducing the expression of the mutant ATN1 protein associated with DRPLA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If symptomatic drugs are used for DRPLA symptoms, then some symptoms can be managed, but treatment satisfaction remains low and the molecular mechanism cannot be addressed
Solution Approach 1:
The invention extracts and targets the specific molecular cause of DRPLA (mutant ATN1 gene with expanded CAG repeats) using antisense oligonucleotides. By designing oligonucleotides that specifically bind to mutant ATN1 mRNA transcripts, the treatment directly removes the harmful molecular mechanism rather than merely managing symptoms, thereby improving both reliability and productivity of treatment
Solution Approach 2:
The antisense oligonucleotide acts as an intermediary molecule that mediates between the mutant ATN1 gene and the cellular machinery. The oligonucleotide binds to mutant ATN1 mRNA, preventing its translation into toxic polyglutamine-expanded proteins, thus providing a targeted molecular intervention that addresses the root cause while maintaining treatment feasibility
2Reliability
If antisense oligonucleotide is designed to target ATN1 mRNA, then direct inhibition of mutant gene is achieved, but specificity between mutant and wild-type ATN1 must be maintained
Solution Approach 1:
The invention applies local quality by designing antisense oligonucleotides that target specific local regions within the ATN1 gene sequence, particularly focusing on the expanded CAG repeat region and adjacent sequences that are unique to the mutant allele. By optimizing the binding region to include the pathogenic expansion, the oligonucleotide achieves high specificity for mutant transcripts while sparing wild-type ATN1 expression
Solution Approach 2:
The invention utilizes parameter changes by modifying the oligonucleotide sequence composition and length to optimize binding affinity and specificity. By adjusting parameters such as GC content, repeat region targeting, and flanking sequence selection, the design achieves differential binding to mutant versus wild-type transcripts, enabling selective inhibition of the pathogenic allele
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 antisense oligonucleotide is expected to provide more effective therapeutic effects for DRPLA by directly inhibiting the mutant ATN1 gene, potentially leading to higher treatment satisfaction with fewer side effects.
Implementation Method 1
an antisense oligonucleotide consisting of 15 to 22 nucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in a target region
Data Source
AI summary
The present invention provides an antisense oligonucleotide that is formed of 15-22 nucleotides and that is complementary to a nucleic acid including at least 15 consecutive bases in a specific target region of a base sequence of SEQ ID NO: 471 (which encodes atrophin 1; ATN1), or a pharmaceutically acceptable salt thereof, or a hydrate thereof.