Tumor-Targeting Trans-Splicing Ribozyme Vector
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Solution Overview
Problem
Current cancer therapies targeting telomerase, specifically hTERT, face challenges due to low expression efficiency and toxicity towards normal cells, as they also affect cells with low telomerase activity like stem cells and regenerating hepatocytes, and require high vector doses for therapeutic effect.
Innovation Solution
A recombinant vector with a CMV promoter, SD/SA sequence, WPRE, and miR-122 target site is used to enhance ribozyme expression specifically in cancer cells, minimizing normal tissue interaction and optimizing cancer cell targeting.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a trans-splicing ribozyme targets hTERT to treat cancer, then cancer cell proliferation is inhibited, but normal cells with low telomerase activity are also affected causing toxicity
Solution Approach 1:
The ribozyme expression system is designed with tissue-specific promoters (liver-specific or prostate-specific promoters) that enable localized expression only in target tissues. This ensures the ribozyme is produced where needed (liver or prostate cancer sites) while avoiding expression in other normal tissues, thereby reducing systemic toxicity while maintaining effective cancer cell targeting
Solution Approach 2:
The invention changes the expression parameters of the ribozyme by using inducible and tissue-specific promoters instead of constitutive promoters. This allows precise spatial and temporal control of ribozyme expression, enabling high expression in cancer tissues while maintaining low or zero expression in normal tissues, thus resolving the toxicity issue
2Object-affected harmful factors
If a tissue-specific promoter is used with trans-splicing ribozyme to improve tissue specificity, then normal cell toxicity is reduced, but expression efficiency becomes very low
Solution Approach 1:
The invention merges multiple promoter elements (tissue-specific promoter sequences) with the ribozyme expression cassette to create a hybrid expression system. This combination maintains the tissue-specificity feature while enhancing overall expression efficiency through optimized promoter architecture and additional regulatory elements
Solution Approach 2:
The expression system uses a composite promoter structure combining multiple regulatory sequences including TATA box, CAAT box, and tissue-specific enhancer elements. This composite promoter design achieves both high expression efficiency and tissue-specificity by integrating multiple functional components that work synergistically
3Reliability
If high vector doses are used to achieve therapeutic effect, then cancer treatment effectiveness is improved, but toxicity to normal tissues increases
Solution Approach 1:
The therapeutic effect is localized to specific tissues through tissue-specific promoter-driven ribozyme expression. This ensures that even at high vector doses, the ribozyme is only actively expressed in target tissues (liver or prostate), preventing systemic toxicity while maintaining effective therapeutic concentrations at the disease site
Solution Approach 2:
The tissue-specific promoter acts as an intermediary element that decouples vector dose from systemic exposure. It allows high vector doses to be administered safely because the promoter ensures ribozyme expression occurs only in target tissues, effectively mediating between dose administration and therapeutic effect while protecting normal tissues
Data Source
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AI summary
The present invention relates to a cancer-specific trans-splicing ribozyme and a use thereof. Since a trans-splicing ribozyme according to the present invention does not act on normal tissue, but is specifically expressed in cancer tissue, it is very safe and has excellent expression efficiency at the post-transcription level, and thus can be effectively used in treatment of cancer. Specifically, as a recombinant vector of the present invention has a CMV promoter and SD/SA and WPRE sequences, the recombinant vector has high ribozyme expression efficiency, and as the recombinant vector of the present invention has miR-122T, it can regulate activity related to miR-122, and it is very safe to utilize. Therefore, the recombinant vector of the present invention can be effectively used in treatment of all types of liver cancer, except some types of liver cancer caused by HCV in which miR-122 expression is highly shown in the cancer tissue in comparison to normal tissue, and the recombinant vector also can be effectively used in treatment of other carcinomas in which miR-122 is not substantially expressed.