C9ORF72 Antisense Transcript Modulation for Neurodegenerative Disease
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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 C9ORF72 hexanucleotide repeat expansions, which contribute to significant morbidity and mortality with limited treatment options.
Innovation Solution
Development of compositions and methods to modulate levels of C9ORF72 antisense transcript in cells and animals using specific inhibitors, including nucleic acids, proteins, or small molecules, to reduce expression of C9ORF72 antisense transcript and associated RAN translation products, thereby addressing the underlying genetic cause of these diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for treating neurodegenerative diseases, then treatment options are limited, but disease progression continues with significant morbidity and mortality
Solution Approach 1:
The patent applies parameter changes by modifying the molecular composition and structure of therapeutic agents. Specifically, it uses antisense oligonucleotides with modified backbones (e.g., phosphorothioate, morpholino) and varied nucleotide sequences to target different regions of C9ORF72 transcripts, thereby creating multiple therapeutic parameters to address the same disease pathway with improved effectiveness and versatility
Solution Approach 2:
The patent segments the therapeutic approach by dividing the C9ORF72 gene transcripts into multiple targetable regions using different antisense oligonucleotide sequences. Each oligonucleotide targets a specific segment of the transcript, allowing for modular treatment strategies that can be combined or selected based on patient-specific disease characteristics
2Duration of action of stationary object
If C9ORF72 antisense transcript levels are reduced using specific inhibitors, then disease progression is slowed, but the complexity of the treatment regimen increases
Solution Approach 1:
The patent achieves universality by designing antisense oligonucleotides that can simultaneously perform multiple functions: they bind to C9ORF72 transcripts to inhibit translation, recruit RNase H for transcript degradation, and potentially modulate RNA processing. This multi-functionality reduces the need for multiple separate therapeutic agents, simplifying the overall treatment regimen while maintaining prolonged disease progression control
Solution Approach 2:
The patent ensures continuity of useful action through the design of oligonucleotides with extended half-lives in biological systems. The modified backbones provide resistance to nucleolytic degradation, allowing continuous suppression of C9ORF72 pathogenic transcripts over extended periods, thereby reducing the frequency of administration and simplifying the treatment regimen
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 antisense transcript levels and associated nuclear foci, slowing disease progression and ameliorating symptoms in neurodegenerative conditions like ALS and FTD, offering a potential therapeutic strategy for currently untreatable disorders.
Implementation Method 1
The antisense oligonucleotide has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 100% complementary to a C9ORF72 antisense transcript
Data Source
AI summary
Disclosed herein are compositions and methods for reducing expression of C9ORF72 antisense transcript in an animal with C9ORF72 antisense transcript specific inhibitors. Such methods are useful to treat, prevent, or ameliorate neurodegenerative diseases in an individual in need thereof. Such C9ORF72 antisense transcript specific inhibitors include antisense compounds.