Modified TATA and CAAT Promoters for Tumor-Selective Viral Expression
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Solution Overview
Problem
Current oncolytic viruses lack tumor-selective replication and therapeutic transgene expression, limiting their effectiveness in treating hyperproliferative disorders and cancers.
Innovation Solution
Development of recombinant viruses with modified TATA and/or CAAT box-based promoters that lack functional TATA and/or CAAT boxes, allowing selective expression in hyperproliferative and non-growth arrested cells, such as cancer cells, using viral vectors like adenovirus, adeno-associated virus, and herpes simplex virus.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional oncolytic viruses are used, then viral replication and cell lysis occur, but tumor-selective replication and therapeutic transgene expression are insufficient
Solution Approach 1:
The patent modifies the promoter parameters by deleting functional TATA and/or CAAT boxes, changing the transcriptional regulation characteristics to achieve tumor-selective expression. This parameter change enables the virus to replicate selectively in hyperproliferative cells while maintaining therapeutic transgene expression.
Solution Approach 2:
The patent extracts and removes the functional TATA box and/or CAAT box from the viral promoter sequence. By taking out these regulatory elements that are active in normal cells, the virus loses the ability to replicate in normal cells while retaining the ability to replicate in cancer cells through alternative promoter mechanisms.
2Ease of operation
If viruses with functional TATA and CAAT boxes are used, then transcription is driven in normal cells, but tumor-selective expression is lost
Solution Approach 1:
The patent inverts the traditional promoter design by removing the functional TATA and/or CAAT boxes that normally drive transcription in healthy cells. This inversion creates a promoter that is inactive in normal cells but active in tumor cells, achieving the opposite effect of conventional promoters.
Solution Approach 2:
The patent applies local quality modification by creating a promoter with different functional characteristics in different cell types. The modified promoter lacks TATA/CAAT boxes in regions where they would normally function, creating local differences in transcriptional activity that enable tumor selectivity.
3Object-generated harmful factors
If oncolytic viruses are administered, then cancer cells are destroyed, but harm to normal cells occurs
Solution Approach 1:
The patent changes the promoter parameters by deleting TATA and/or CAAT boxes, which fundamentally alters the transcriptional regulation. This parameter change ensures the virus only replicates in hyperproliferative cancer cells while remaining inactive in normal cells, eliminating harm to normal tissues.
Solution Approach 2:
The patent converts the harmful effect of viral replication in normal cells into a benefit by removing the TATA/CAAT boxes. The virus naturally loses the ability to replicate in normal cells (which was harmful) and gains tumor-selectivity (which is beneficial), turning a potential harm into a selective advantage.
Data Source
AI summary
The invention provides, e.g., a recombinant virus comprising (i) a modified TATA box-based promoter, and/or (ii) a modified CAAT box-based promoter operably linked to a gene, wherein the modified TATA box-based promoter and/or modified CAAT box-based promoter lacks a functional TATA box and/or CAAT box and permit selective expression of the gene in a hyperproliferative cell. The recombinant viruses can be used to treat cell proliferative diseases and disorders, including certain forms of cancer.