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Liver-specific viral promoters and methods of using the same

A promoter and a technology for synthesizing polynucleotides, which are applied to liver-specific viral promoters and the field of their use, and can solve problems such as reduced curative effect

Pending Publication Date: 2021-08-31
优尼科IP有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, targeting the liver is still not absolutely precise, and off-target delivery and expression may lead to reduced efficacy or complications

Method used

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  • Liver-specific viral promoters and methods of using the same
  • Liver-specific viral promoters and methods of using the same
  • Liver-specific viral promoters and methods of using the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0231] Example 1 - Determination of constitutive promoter elements

[0232] A meta-analysis of hepatocyte datasets was performed to identify candidate genes for cis-element selection. Microarray and NGS datasets and scientific literature were consulted to identify genes expressed at very high levels in target cell types.

Embodiment 2

[0233] Example 2 - Selection of cis-regulatory elements contained in a synthetic promoter library in hepatocytes

[0234] Once a suitable liver-associated gene set has been identified, the promoter regions of the selected genes are next analyzed to identify cis-regulatory elements (CREs) and other features in the selected promoters responsible for transcriptional regulation. Three methods were used to determine the cis-elements to be incorporated into the synthetic promoter library construction, resulting in the selection of at least SEQ ID NO: 1-19.

[0235] The identified cis-elements were used separately to create different libraries. Relevant compound elements regulating liver-specific genes were identified through the Liver-Specific Gene Promoter Database (LSGPD) and literature searches. These composite elements were then used to design new synthetic promoters.

Embodiment 3

[0236] Example 3 - Creation of Liver-Specific Synthetic Promoter Library Screening Vectors

[0237] The screening vector was based on the pUC19 backbone (synthetic promoter library+core promoter elements+GFP). Synthetic promoter libraries were cloned upstream of the minimal promoter sequence. This sequence contains elements necessary for the recruitment of the RNA polymerase II complex and contains the transcription initiation site. The minimal promoter sequence revealed basal transcriptional activity and the library sequence cloned upstream was designed to enhance its activity and specificity.

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Abstract

The present invention relates to promoters that function specifically or preferentially in the liver. These promoters are capable of enhancing liver-specific expression of genes.The invention also relates to expression constructs, vectors and cells comprising such liver- specific promoters, and to methods of their use.The present invention future relates to adeno-associated virus (AAV) gene therapy vectors comprising the liver-specific promoters, therapeutic agents comprising the liver-specific promoters, and methods using the same.

Description

technical field [0001] Promoters that function specifically or preferentially in the liver are described herein. Also disclosed herein are adeno-associated virus (AAV) gene therapy vectors comprising liver-specific promoters, therapeutic agents comprising liver-specific promoters, and methods of use thereof. Background technique [0002] The following discussion is provided to assist the reader in understanding the present disclosure and is not an admission that it describes or constitutes prior art therefor. [0003] Studies of the hepatic uptake of DNA molecules and vectors (such as viral vectors) used in gene therapy have shown that the liver has a high capacity to uptake these from circulation. In fact, it is well known that many viral vectors used in gene therapy, including adeno-associated virus (AAV) vectors, can be efficiently taken up in the liver, and thus this organ is relatively easy to target compared to other organs. [0004] Furthermore, because the liver pl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/11C07K14/755C12N15/79
CPCC07K14/755C12N15/86C12N15/85C12N2750/14141C12N2830/008A61P1/16A61K48/00C12N2750/14123C12N2750/14143C12N2750/14171
Inventor J·卢贝尔斯基D·J·F·杜普莱西斯Y·P·刘O·特布雷克J·M·伊格莱西亚斯冈萨雷斯R·弗拉泽M·罗伯茨
Owner 优尼科IP有限公司
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