Oncoselective mRNA Translation via Read-Through Motifs
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cancer therapies face challenges in achieving oncoselective expression of translatable nucleic acids, leading to inefficient targeting of cancer cells and potential toxic effects on non-tumor cells due to lack of specificity.
Innovation Solution
Incorporation of oncoselective translation sequence elements, such as read-through motifs, into nucleic acids to enhance selective translation in cancer cells, utilizing structural features like high G-C content, stem loops, and pseudoknots to induce stop codon read-through, ensuring payload expression primarily in oncogenic ribosomes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional nucleic acid delivery is used, then delivery efficiency is improved, but oncoselectivity deteriorates leading to toxic effects on non-tumor cells
Solution Approach 1:
The patent introduces oncoselective translation sequence elements (such as read-through motifs with specific G-C content, stem loops, and pseudoknots) that create localized functional differences in the nucleic acid sequence. These elements are positioned specifically within the open reading frame to interact with oncogenic ribosomes, enabling the therapeutic payload to be selectively expressed only in cancer cells while maintaining efficient delivery to both cancer and non-cancer cells.
2Reliability
If therapeutic payloads with high toxicity are used, then treatment efficacy is improved, but harmful effects on non-cancer cells worsen
Solution Approach 1:
The patent uses oncoselective translation sequence elements as intermediary components between the nucleic acid delivery system and the therapeutic payload. These sequence elements act as selective gatekeepers that allow translation of the payload only in cancer cells with oncogenic ribosomes, thereby enabling the use of highly toxic therapeutic agents (such as suicidal proteins or cytotoxic drugs) without harming non-cancer cells.
3Productivity
If conventional translation sequences are used, then translation efficiency is improved, but oncoselectivity deteriorates
Solution Approach 1:
The patent creates a composite nucleic acid structure that combines conventional translation-efficient sequences with newly designed oncoselective translation sequence elements. The composite includes an open reading frame with optimized Kozak sequences for efficient initiation, combined with downstream read-through motifs containing specific structural features (stem loops, pseudoknots, high G-C content) that provide oncoselectivity. This composite design achieves both high translation efficiency and cancer cell specificity.
Data Source
AI summary
The present disclosure provides technologies for achieving oncoselective translation. The use of two complementary pipelines to study the translation landscapes of cancer vs. normal cells described in this disclosure enables identification of oncoselective sequence motifs that can be used to engineer synthetic DNAs or mRNA constructs for cancer cell specific protein expression. The present disclosure describes the features of oncoselective motifs and provides embodiments of modular oncoselective construct designs that can be used to encode payloads of high therapeutic interest.