FUS Antisense Oligonucleotides for Proteinopathy Progression Control
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Solution Overview
Problem
Current treatments for neurological conditions associated with FUS proteinopathy, such as ALS and FTLD, are limited to symptom management with no effective means to slow or halt disease progression, and there is a need for treatments that target the underlying pathogenic mechanisms of FUS expression and mislocalization.
Innovation Solution
The use of antisense oligonucleotides (AONs) specifically designed to target and inhibit FUS pre-mRNA expression, including sequences that induce alternative splicing and reduce FUS protein levels, using phosphorodiamidate morpholino oligomers to treat diseases associated with FUS proteinopathy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If current symptom management treatments are used, then patient comfort is improved, but disease progression cannot be slowed or halted
Solution Approach 1:
The patent extracts and targets the specific pathogenic FUS protein and its mislocalization to the cytoplasm as the root cause of disease. By using antisense oligonucleotides to specifically reduce FUS expression and prevent cytoplasmic accumulation, the treatment addresses the underlying mechanism rather than merely managing symptoms, thereby slowing disease progression while maintaining patient comfort.
Solution Approach 2:
The patent applies preliminary action by preventing FUS mislocalization and aggregation before they can cause neuronal damage. The antisense oligonucleotides are administered to reduce FUS expression proactively, preventing the formation of toxic cytoplasmic aggregates and their propagation, thereby slowing disease progression before severe symptoms manifest.
2Reliability
If FUS expression is reduced using AONs, then disease progression is slowed, but new treatment modalities are required
Solution Approach 1:
The patent uses antisense oligonucleotides as intermediary molecules that mediate between the therapeutic goal (reducing FUS expression) and the biological target (FUS pre-mRNA). These AONs serve as deliverable therapeutic agents that can be administered clinically to achieve FUS reduction, providing a practical bridge between molecular mechanism and clinical treatment without requiring complex direct protein-targeting approaches.
Solution Approach 2:
The patent applies parameter changes by modifying the FUS gene expression level through antisense oligonucleotide binding to pre-mRNA. This changes the transcriptional output parameter, reducing FUS protein production at the source. The approach transforms the treatment strategy from managing downstream effects to altering upstream gene expression, providing a controllable parameter for disease modification.
3Reliability
If FUS mislocalization to cytoplasm is prevented, then neuronal function is protected, but FUS protein levels must be precisely controlled
Solution Approach 1:
The patent applies local quality by specifically targeting FUS pre-mRNA sequences that lead to cytoplasmic mislocalization and aggregation. The antisense oligonucleotides are designed to bind to specific regions of FUS pre-mRNA, selectively preventing the formation of toxic cytoplasmic aggregates while allowing normal nuclear FUS function to proceed. This localized intervention protects neuronal function without requiring complete FUS elimination.
Solution Approach 2:
The patent applies partial action by reducing FUS expression to a degree that is sufficient to prevent cytoplasmic mislocalization and aggregate formation, but not necessarily to completely eliminate FUS protein. The goal is to achieve the minimal effective reduction that prevents toxicity while maintaining necessary FUS function for neuronal health, avoiding excessive reduction that could have unintended consequences.
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 AONs effectively reduce FUS expression, potentially slowing symptom progression and improving survival in patients with FUS-related neurological conditions by targeting the underlying cause of the disease, including ALS and FTLD.
Implementation Method 1
The AON has a nucleobase sequence that is complementary to at least 1 or more contiguous nucleobases in a target FUS pre-mRNA
Data Source
AI summary
The present invention relates to the field of antisense oligonucleotides used to reduce expression of the FUS gene which encodes the FUS protein. The invention also provides pharmaceutical compositions and methods to treat the effects of a disease associated with FUS proteinopathy, high FUS expression or FUS mutation by administration of antisense oligonucleotides and therapeutic compositions comprising AON's targeted to FUS.