Oligomeric Compounds Modulating FMR1 Expression
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Solution Overview
Problem
Current treatments for fragile X-spectrum disorders, including Fragile X Syndrome, Fragile X-Associated Tremor/Ataxia Syndrome, and Fragile-X-Associated Premature Ovarian Failure, lack effective options to address symptoms and halt disease progression.
Innovation Solution
Development of oligomeric compounds, specifically modified oligonucleotides, to reduce Repeat Associated Non-AUG (RAN) translation products and increase FMR1 RNA and FMRP synthesis, thereby ameliorating symptoms such as intellectual disability, physical abnormalities, anxiety, and neuronal death.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for fragile X-spectrum disorders, then no effective treatment options are available, but the disease progresses without intervention
Solution Approach 1:
The patent extracts and targets the harmful RAN translation products (polyglycine, polyalanine, polyarginine proteins) produced from CGG repeats in the FMR1 gene. By specifically eliminating these toxic proteins through oligomeric compounds, the treatment addresses the root cause of neuronal damage and disease progression in fragile X-spectrum disorders.
Solution Approach 2:
The patent employs oligomeric compounds that modify the expression parameters of FMR1 RNA and FMRP synthesis. These compounds change the translational parameters by suppressing RAN translation while enhancing canonical AUG-initiated translation, thereby altering the protein production profile to be beneficial for treating fragile X-spectrum disorders.
2Quantity of substance
If CGG repeats are present in the FMR1 locus, then FMR1 transcription occurs, but RAN translation produces harmful proteins
Solution Approach 1:
The patent converts the harmful effect of CGG repeats into a beneficial outcome by selectively suppressing RAN translation while preserving canonical translation. The oligomeric compounds enable the cell to distinguish between harmful non-AUG initiated translation and beneficial AUG-initiated translation, thereby converting the previously harmful repeat structure into a manageable element that can be therapeutically addressed.
3Reliability
If FMRP synthesis is impaired, then neuronal function is compromised, but current treatments cannot restore it
Solution Approach 1:
The patent introduces oligomeric compounds as intermediary agents that mediate between the FMR1 gene and the cellular translation machinery. These compounds act as modulators that enhance FMRP synthesis by suppressing RAN translation and promoting canonical translation pathways, thereby restoring neuronal function without requiring direct gene therapy or complex interventions.
Data Source
AI summary
Provided are methods for increasing the amount or activity of FMR1 RNA, and in certain instances of increasing the amount of FMRP protein, in an animal. Such methods are useful to prevent or ameliorate at least one symptom of a Fragile X-Spectrum disorder. Such Fragile X-Spectrum disorders include FXS, FXTAS, and FXPOI.