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Recombinant oncolytic gene adenovirus, and construction method and application thereof

A construction method and adenovirus technology, applied in the field of recombinant oncolytic gene-adenovirus, can solve the problems of limited effect, accidental injury to normal human cells, and weak effect, and achieve high cancer specificity, excellent anticancer effect, and low toxicity Effect

Pending Publication Date: 2022-01-18
SHANGHAI YUANSONG BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current various gene carriers cannot specifically select tumor cells in the human body, nor can they efficiently express anti-cancer genes in tumor cells, resulting in weak gene therapy effects and the possibility of accidentally injuring normal human cells
Treatment of cancer with gene therapy alone or tumor-specific viruses has limited efficacy

Method used

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  • Recombinant oncolytic gene adenovirus, and construction method and application thereof
  • Recombinant oncolytic gene adenovirus, and construction method and application thereof
  • Recombinant oncolytic gene adenovirus, and construction method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1. Recombinant adenovirus Onco Ad - Construction of P28-E1A-ΔE1B-IL-24

[0043] This example mainly describes the construction method of a recombinant oncolytic adenovirus OncoAd-P28-E1A-ΔE1B-IL-24.

[0044] In order to improve the tumor specificity of adenovirus, the wild-type promoter of the E1A region, an important element controlling adenovirus replication, was replaced with the liver cancer-specific promoter P28GANK (P28), and the E1B region of the adenovirus was deleted, and IL-24 was inserted. The expression cassette is used to improve the killing effect of the virus on tumor cells. Recombinant oncolytic adenovirus Onco Ad The structure diagram of -P28-E1A-ΔE1B-IL-24 and the corresponding empty virus is shown in figure 1 .

[0045] (1) Construction of the recombinant small plasmid pShuttle-P28-E1A-ΔE1B-IL-24: PCR was performed using the pZD55-IL-24 plasmid (see Chinese patent ZL 200510026151.1) as a template, and the expression cassette of IL-24 was c...

Embodiment 2

[0051] Example 2. Recombinant oncolytic adenovirus Onco Ad Targeted killing of liver cancer cells by -P28-E1A-ΔE1B-IL-24

[0052] To detect recombinant oncolytic adenovirus Onco Ad -Whether P28-E1A-ΔE1B-IL-24 can target and kill liver cancer cells, normal liver cells QSG-7701, liver cancer cells Huh-7 and Hep3B were selected for in vitro killing tests. The above cells were mixed according to 1×10 per well 5 A 24-well plate was spread at the density of each cell, and after the cells adhered to the wall, the Onco Ad -P28-E1A-ΔE1B and Onco Ad -P28-E1A-ΔE1B-IL-24 infected cells were stained with crystal violet 72 hours after infection. Experimental results such as Figure 7 As shown, the recombinant oncolytic adenovirus Onco Ad -P28-E1A-ΔE1B and Onco Ad -P28-E1A-ΔE1B-IL-24 has almost no killing ability to normal liver cells QSG-7701, and only when the virus titer is as high as 100 MOI can it produce obvious killing effect, showing good safety. And Onco Ad -P28-E1A-ΔE1B an...

Embodiment 3

[0054] Example 3. Recombinant Oncolytic Adenovirus Onco Ad -P28-E1A-ΔE1B-IL-24 has a synergistic effect in combination with JQ1

[0055] BRD4, a member of the bromodomain and extraterminal domain (BET) family of proteins, is widely present in mammals and is involved in the regulation of the cell cycle. In recent years, studies have found that BRD4 is related to the occurrence of acute myeloid leukemia, breast cancer, melanoma, Burkitt lymphoma, colon cancer and other cancers. BRD4 shRNA or BET inhibitors can induce cell cycle arrest and apoptosis in these cancers. and cell differentiation, showing strong anticancer activity. According to our previous research progress, one of the main ways for oncolytic adenovirus to directly kill tumors is to induce apoptosis. Therefore, we can try to combine BRD4 inhibitor with oncolytic adenovirus, which may have unexpected efficacy.

[0056] JQ-1 is a BRD4-specific inhibitor. For the first time, we tried to combine JQ1 with recombinant o...

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Abstract

The invention provides a recombinant oncolytic gene adenovirus, and a construction method and application thereof. The promoter of the recombinant oncolytic gene adenovirus comprises a liver cancer specific promoter. The recombinant oncolytic gene adenovirus comprises a coding nucleotide sequence of IL-24. The provided recombinant oncolytic gene adenovirus has efficient cancer specificity, the recombinant oncolytic adenovirus constructed by using the recombinant oncolytic gene adenovirus has low toxicity to normal cells and good cancer cell killing effect, and has a synergistic effect when being combined with a BRD4 inhibitor, and the anti-cancer effect is superior to that of common recombinant oncolytic adenovirus.

Description

technical field [0001] The invention belongs to the technical field of recombinant oncolytic gene-adenovirus, and in particular relates to a recombinant oncolytic gene adenovirus and a construction method and application thereof. Background technique [0002] Cancer seriously affects human health and development. Affected by medical and environmental conditions, China's cancer mortality rate is higher than the global average. Traditional tumor therapy has the disadvantages of poor efficacy, high mortality and high prognosis recurrence rate. Therefore, people have begun to place high hopes on emerging tumor therapy methods. Emerging strategies for the treatment of tumors are also under constant development, and currently more recognized strategies include immunotherapy, gene therapy, oncolytic virus therapy, etc. Various current gene vectors cannot specifically select tumor cells in the human body, nor can they express anti-cancer genes efficiently in tumor cells, resulting ...

Claims

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Application Information

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IPC IPC(8): C12N7/01C12N15/861A61K48/00A61K38/20A61K45/06A61P35/00C12R1/93
CPCC12N7/00C07K14/54C07K14/005C12N15/86A61K48/0025A61K48/005A61K48/0058A61K38/20A61K45/06A61P35/00C12N2710/10321C12N2710/10322C12N2710/10352
Inventor 方先龙章康健曹雪萍顾锦法刘新垣
Owner SHANGHAI YUANSONG BIOTECHNOLOGY CO LTD
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