Antisense Oligonucleotides Targeting FUS RNA for Neurodegenerative Disease
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Solution Overview
Problem
Current therapies are lacking for effectively treating amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), particularly in reducing the levels of FUS RNA and protein, which are associated with these neurodegenerative conditions.
Innovation Solution
Development of compounds, methods, and pharmaceutical compositions that specifically target FUS RNA and protein, including oligomeric compounds comprising modified oligonucleotides that are complementary to FUS nucleic acid, to reduce their levels in cells and subjects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If current therapies are used, then treatment for ALS and FTLD is provided, but FUS RNA and protein levels are not effectively reduced
Solution Approach 1:
The patent extracts and targets FUS RNA specifically using antisense oligonucleotides that bind to complementary sequences in the FUS gene transcript. This extraction approach removes FUS RNA from the cell, preventing protein synthesis and reducing FUS protein levels, thereby directly addressing the technical problem of ineffective current therapies.
Solution Approach 2:
The patent modifies the chemical structure of oligonucleotides by incorporating modified sugar moieties (such as 2'-O-methoxyethyl, 2'-O-methyl, or bicyclic sugars) and phosphorothioate linkages. These parameter changes in the oligonucleotide structure enhance binding affinity, stability, and cellular uptake, enabling effective reduction of FUS RNA and protein levels that current therapies cannot achieve.
2Reliability
If FUS RNA and protein levels are reduced, then therapeutic effect is achieved, but compound specificity and safety must be maintained
Solution Approach 1:
The patent designs antisense oligonucleotides with specific nucleotide sequences that are complementary to particular regions of the FUS gene transcript. This local targeting approach ensures that the therapeutic effect is concentrated on FUS RNA specifically, minimizing off-target effects. The modified sugar moieties and phosphorothioate linkages further enhance this specificity by improving binding selectivity to the FUS sequence.
Solution Approach 2:
The modified oligonucleotide acts as an intermediary that binds to FUS RNA through complementary base pairing. This intermediary mechanism allows for precise targeting and reduction of FUS protein levels while the modified chemical structure ensures safety and reduces off-target effects. The oligonucleotide serves as a controlled mediator between the therapeutic agent and the FUS protein pathway.
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 compounds and compositions demonstrate the ability to ameliorate symptoms and hallmarks of ALS and FTLD by reducing FUS RNA and protein levels, thereby providing a potential therapeutic approach for these diseases.
Implementation Method 1
oligonucleotides, which consist of linked nucleosides... the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage... consisting of 12 to 50 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to an equal length portion of a FUS nucleic acid
Data Source
AI summary
Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of FUS RNA in a cell or subject, and in certain instances reducing the amount of FUS protein in a cell or subject. These compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative condition. Such symptoms and hallmarks include muscle weakness and fatigue, protein aggregates in the central nervous system, and speech difficulties and behavioral abnormalities. Non-limiting examples of neurodegenerative conditions that benefit from these compounds, methods, and pharmaceutical compositions are amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).