eIF3 Modulation for Selective Control of RAN Translation
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Solution Overview
Problem
The mechanism of repeat-associated non-ATG (RAN) translation remains poorly understood, particularly in relation to disease pathogenesis, and additional cis- and trans-factors involved in this process are yet to be elucidated, leading to challenges in managing diseases associated with RAN protein accumulation.
Innovation Solution
Modulating eukaryotic initiation factor 3 (eIF3) using agents such as proteins, nucleic acids, or small molecules, specifically targeting eIF3 subunits like eIF3f or eIF3m, to inhibit or enhance RAN protein translation in cells, thereby treating diseases associated with RAN protein accumulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If RAN translation is enhanced to produce therapeutic proteins, then protein production increases, but RAN protein toxicity accumulates causing cellular damage
Solution Approach 1:
The patent uses eIF3 modulating agents as intermediaries to control RAN translation. These agents specifically target the eIF3 complex involved in RAN translation initiation, allowing selective modulation of RAN protein production without affecting other cellular processes. This mediator approach enables precise control to achieve therapeutic protein production while avoiding toxic accumulation.
Solution Approach 2:
The patent applies parameter changes by modulating eIF3 activity levels to control RAN translation efficiency. By adjusting the activity of eIF3 (a key translation initiation factor), the system can optimize RAN protein production to therapeutic levels while preventing excessive accumulation that would cause toxicity. This parameter control is achieved through eIF3 modulating agents that adjust translation initiation rates.
2Quantity of substance
If eIF3 is modulated to inhibit RAN translation, then RAN protein levels decrease, but normal translation processes may be affected
Solution Approach 1:
The patent applies local quality by developing eIF3 modulating agents that specifically target RAN translation initiation without broadly affecting normal translation. The modulators are designed to interact with specific components of the RAN translation machinery or specific RNA structures associated with RAN repeats, thereby selectively reducing RAN protein levels while preserving normal protein synthesis pathways.
Solution Approach 2:
The eIF3 modulating agents serve as intermediaries that specifically intervene in RAN translation processes. These agents target the unique features of RAN translation (such as repeat-containing RNA structures or specific initiation mechanisms) to reduce RAN protein levels while leaving canonical translation largely unaffected, thus maintaining reliability of normal translation functions.
3Quantity of substance
If larger repeat expansions are present, then RAN protein accumulation increases, but disease severity worsens due to enhanced toxicity
Solution Approach 1:
The patent applies preliminary anti-action by using eIF3 modulating agents to preemptively block RAN translation before excessive protein accumulation occurs. By interfering with the translation initiation process at the eIF3 level, the system prevents the formation of toxic RAN protein aggregates before they can reach harmful concentrations, thereby counteracting the enhanced toxicity associated with larger repeat expansions.
Solution Approach 2:
The patent converts the harmful effect of repeat expansions into a therapeutic opportunity by targeting the eIF3 machinery that drives RAN translation. The same translation machinery that causes pathological protein accumulation when dysregulated becomes the target for therapeutic intervention, where modulating eIF3 activity can reduce toxic protein levels and mitigate disease severity.
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.