eIF3 Subunit Modulation for Selective RAN Translation Inhibition
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Solution Overview
Problem
The mechanism of repeat-associated non-ATG (RAN) translation in diseases associated with nucleotide expansions remains poorly understood, and existing treatments fail to effectively modulate the toxicity caused by RAN protein accumulation.
Innovation Solution
Modulating eukaryotic initiation factor 3 (eIF3) using agents such as antibodies, siRNA, or small molecules to regulate RAN protein translation, particularly targeting specific eIF3 subunits like eIF3f and eIF3m, to reduce or inhibit RAN protein expression in cells and tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-generated harmful factors
If eIF3 is modulated to inhibit RAN translation, then RAN protein accumulation is reduced, but normal translation initiation may be affected
Solution Approach 1:
The patent applies local quality by developing eIF3 modulators that selectively target RAN translation initiation while preserving normal translation. This is achieved through specific molecular interactions that distinguish RAN translation mechanisms from canonical translation, allowing localized inhibition of harmful RAN protein production without broadly affecting cellular protein synthesis machinery
Solution Approach 2:
The patent uses small molecule compounds as intermediaries that bind to eIF3 and modulate its function specifically in RAN translation contexts. These small molecules act as mediators between the eIF3 complex and the translation machinery, fine-tuning eIF3 activity to suppress RAN translation while maintaining normal translation through controlled molecular interactions
2Quantity of substance
If larger repeat expansions are targeted, then RAN protein accumulation increases, but therapeutic intervention becomes more challenging
Solution Approach 1:
The patent extracts the translation initiation step as a specific therapeutic target by modulating eIF3 function. By intervening at the initiation stage rather than dealing with the entire translation process or downstream effects, the approach simplifies therapeutic intervention despite the complexity introduced by large repeat expansions. This extraction of the critical control point makes the therapy more manageable
Solution Approach 2:
The patent employs parameter changes by using small molecule compounds that alter the functional parameters of eIF3. These compounds modify eIF3's activity, binding affinity, or conformational state to selectively inhibit RAN translation initiation. By changing the functional parameters of eIF3 rather than targeting the repeat expansion directly, the therapy becomes more tractable despite large repeat sizes
Data Source
AI summary
Methods and compositions for modulating repeat non-ATG protein (RAN protein) translation are provided. In some aspects, the disclosure relates to methods for treating a subject having a disease associated with RAN protein translation by administering the subject a modulator of eIF3 or an eIF3 subunit, or an antibody that bind to a RAN protein.