Modified Oligonucleotides Targeting C9ORF72 mRNA
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Solution Overview
Problem
Current therapies are ineffective for treating neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), particularly those associated with the C9ORF72 gene, which has a common genetic cause due to a hexanucleotide repeat expansion.
Innovation Solution
Development of compositions and methods involving antisense compounds, specifically modified oligonucleotides that target and reduce C9ORF72 mRNA and protein levels, including single-stranded modified oligonucleotides complementary to C9ORF72 nucleic acid, to inhibit the expression of pathogenic associated mRNA variants and associated RAN translation products.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for treating neurodegenerative diseases, then treatment is provided, but the therapies are ineffective for diseases associated with C9ORF72 gene mutations
Solution Approach 1:
The patent applies parameter changes by modifying the oligonucleotide structure with specific chemical modifications (2'-O-methoxyethyl groups, phosphorothioate linkages) to enhance binding affinity and stability, thereby improving therapeutic effectiveness for C9ORF72-associated diseases where conventional therapies fail
Solution Approach 2:
The antisense oligonucleotide acts as an intermediary molecule that binds to C9ORF72 mRNA to prevent translation, serving as a mediator between the genetic defect and therapeutic intervention, enabling treatment of diseases that were previously untreatable
2Reliability
If antisense compounds are developed to target C9ORF72 mRNA, then pathogenic mRNA variants are reduced, but device complexity increases
Solution Approach 1:
The patent applies local quality by designing the oligonucleotide to bind to a specific local region (intron 1 containing the hexanucleotide repeat expansion) of the C9ORF72 pre-mRNA, enabling selective reduction of pathogenic variants while preserving normal gene function through localized targeting
Solution Approach 2:
The antisense compound employs composite material structure combining DNA backbone with modified sugar moieties (2'-O-methoxyethyl) and phosphate linkages (phosphorothioate), creating a chimeric molecule that integrates properties of different nucleic acid components to achieve both stability and specificity
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 approach effectively reduces C9ORF72 mRNA and protein levels, thereby potentially slowing the progression or treating neurodegenerative diseases like ALS and FTD by targeting the underlying genetic cause, offering a therapeutic option for these currently untreatable conditions.
Implementation Method 1
antisense compounds, specifically modified oligonucleotides that target and reduce C9ORF72 mRNA and protein levels, including single-stranded modified oligonucleotides complementary to C9ORF72 nucleic acid
Data Source
AI summary
Disclosed herein are compositions and methods for reducing expression of C9ORF72 mRNA and protein in an animal. Such methods are useful to treat, prevent, ameliorate, or slow progression of neurodegenerative diseases in an individual in need thereof.