CN110075131B - Application of Zika virus attenuated strain in treatment of brain glioma - Google Patents
Application of Zika virus attenuated strain in treatment of brain glioma Download PDFInfo
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- CN110075131B CN110075131B CN201810076027.7A CN201810076027A CN110075131B CN 110075131 B CN110075131 B CN 110075131B CN 201810076027 A CN201810076027 A CN 201810076027A CN 110075131 B CN110075131 B CN 110075131B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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Abstract
The invention relates to the field of tumor treatment and discloses application of attenuated strains of Zika virus in treatment of glioma. By using attenuated strains of Zika virus, the invention can effectively treat the brain glioma and inhibit the development of the brain glioma.
Description
Technical Field
The invention relates to the field of tumor treatment, in particular to application of attenuated strains of Zika virus in treatment of glioma.
Background
Glioblastomas (glioblastomas) are a common highly invasive primary brain tumor. The life cycle of glioma patients is short, and the median life cycle of high-grade glioma patients is only about 1 year. The current treatment scheme of the brain glioma mainly comprises surgical treatment, radiotherapy and chemical drug treatment, but the recurrence rate after the treatment is high, and the treatment effect is poor. One of the main reasons is that within a brain glioma, there is a small population of cells called Glioma Stem Cells (GSCs), which have a strong resistance to radiotherapy and chemotherapy, are self-renewing and immortalizing, and are considered to be a group of cells that determines the development of a brain glioma. Therefore, glioma stem cells are considered to be a key target for brain glioma therapy.
Zika virus (ZIKV) belongs to the flaviviridae genus of the family flaviviridae, mainly including two types, an african strain and an asian strain, and an asian strain of zika virus has recently been demonstrated to be associated with fetal microcephaly. The main reason is that the strain can infect the immature central nervous system and mainly infect Neural Precursor Cells (NPCs) therein, and eventually cause such cells to differentiate or die. However, this virus strain generally causes only mild clinical symptoms such as short-term fever and the like in case of adult infection. The current research is mainly focused on the development of Zika virus vaccines, and further elucidation of the application of Zika virus itself is lacking.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provides an application of an attenuated strain of Zika virus in treating glioblastomas (glioblastomas).
In order to achieve the above object, the present invention provides, in a first aspect, use of an attenuated strain of Zika virus having a deletion of a portion of nucleotides compared to wild-type Zika virus genomic RNA, in the manufacture of a medicament for treating glioma, wherein the deleted nucleotides include at least the nucleotides located at position 10650-10659 in the wild-type Zika virus genomic RNA.
In a second aspect, the invention provides a pharmaceutical composition for treating brain glioma, which comprises an attenuated strain of Zika virus and a pharmaceutically acceptable adjuvant.
In a third aspect, the invention provides an attenuated strain of Zika virus for use in the treatment of brain gliomas.
In a fourth aspect, the present invention provides a method of treating brain glioma, the method comprising: administering an effective amount of an attenuated strain of Zika virus or an effective amount of the above pharmaceutical composition to a subject having a glioma.
By using attenuated strains of Zika virus, the invention can effectively treat the brain glioma and inhibit the development of the brain glioma.
Drawings
FIG. 1 is the neurovirulence characteristics results of the attenuated strains of Zika virus of example 1;
FIG. 2 is the results of treatment of an attenuated strain of Zika virus in example 2 for gliomas in an animal model (in vivo imaging);
FIG. 3 is the results of treatment of an attenuated strain of Zika virus in example 2 for gliomas in an animal model (survival time);
FIG. 4 is the results of treatment of an attenuated strain of Zika virus in example 3 for brain gliomas in an animal model (glioma size).
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
In one aspect, the invention provides the use of an attenuated strain of Zika virus having a deletion of a portion of nucleotides compared to wild-type Zika virus genomic RNA in the manufacture of a medicament for the treatment of glioma, wherein the deleted nucleotides comprise at least the nucleotides located at position 10650-10659 (3' noncoding region) of the wild-type Zika virus genomic RNA.
In the present invention, the object of the present invention can be achieved by the attenuated strain of Zika virus having the deletion of the above-mentioned nucleotide, and in addition, any one of the nucleotides located at positions 10630-10674 in the genomic RNA of wild-type Zika virus may be mutated (deleted), but preferably, the Zika virus has only the deletion of the above-mentioned ten nucleotides (positions 10650-10659). Construction of a virus in which a part of the nucleotide of the genomic RNA is deleted is routinely performed by those skilled in the art, and thus will not be described herein.
In the present invention, the wild-type Zika virus is preferably a Zika virus having Genebank accession number KU955593 (abbreviated as KU 955593). That is, according to a preferred embodiment of the present invention, the attenuated strain of Zika virus is an attenuated strain obtained by deletion of nucleotides at 10650-10659 of KU 955593.
The attenuated Zika virus strain can effectively (in vitro) inhibit the growth of glioma stem cells, so that the invention also relates to the application of the attenuated Zika virus strain in (in vitro) inhibition of glioma stem cells.
In another aspect, the present invention provides a pharmaceutical composition for treating glioma, comprising an attenuated strain of Zika virus having a deletion of a portion of nucleotides compared to wild-type Zika virus genomic RNA, wherein the deleted nucleotides comprise at least the nucleotides located at positions 10650-10659 in the wild-type Zika virus genomic RNA, and a pharmaceutically acceptable excipient. The attenuated strains of Zika virus are described in detail above and will not be described further. The content of the attenuated strain of Zika virus in the pharmaceutical composition may be conventionally selected, and may be, for example, 104-5×104PFU/g。
The term "pharmaceutically acceptable" means not biologically or otherwise undesirable. The term "adjuvant" refers to any substance present in a pharmaceutical formulation that is not an active ingredient, including diluents, binders, lubricants, disintegrants, colorants, emulsifiers, pH buffers, preservatives, and the like. The auxiliary materials used in the invention can be various conventional auxiliary materials used for pharmacy.
According to a preferred embodiment of the invention, the pharmaceutical composition further comprises an auxiliary agent useful for the treatment of said brain glioma. The adjuvant drug can be chemical drug, such as temozolomide, elemene, etc., or other drug with above curative effect.
In yet another aspect, the present invention provides an attenuated strain of Zika virus for use in the treatment of brain gliomas, wherein said attenuated strain of Zika virus has a deletion of a portion of nucleotides compared to wild-type Zika virus genomic RNA, wherein the deleted nucleotides comprise at least the nucleotides located at position 10650-10659 of wild-type Zika virus genomic RNA.
In addition, the present invention provides a method for treating brain glioma, comprising: administering to a subject having a brain glioma an effective amount of an attenuated strain of Zika virus having a deletion of a portion of nucleotides compared to wild-type Zika virus genomic RNA, wherein the deleted nucleotides comprise at least the nucleotides located at position 10650-10659 in the wild-type Zika virus genomic RNA, or an effective amount of the pharmaceutical composition as described previously. Wherein, the effective amount refers to the effective dose of the drug.
The subject may be a mammal, particularly a primate (e.g. human or monkey) or a rodent (e.g. mouse), commonly suffering from said brain glioma.
In the present invention, the attenuated strain of Zika virus or the pharmaceutical composition may be administered in any conventional manner, such as topically. One skilled in the art can prepare the attenuated strain of Zika virus or the pharmaceutical composition containing the attenuated strain of Zika virus into different dosage forms according to the specific administration mode.
The dose to be administered may be a dose (effective amount) conventional in the art, and may be determined according to various parameters, particularly according to the age, body weight, sex and health condition of the subject. For example, for female, BALB/c nude mice aged 3-4 weeks and weighing 15-20g, each of the attenuated strains of Zika virus may be used in an amount of 1PFU/kg body weight to 5X 104PFU/kg body weight (intracranial injection).
The present invention will be described in detail below by way of examples.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
This example illustrates the neurovirulence characteristics of attenuated strains of Zika virus used in the present invention.
Attenuated strains of Zika virus (deletion of nucleotide 10650-10659, see Chao Shan et al, A live-attenuated Zika virus vaccine peptides antibiotic vaccines antibiotic infection in mice models, Nature Medicine,2017) and Japanese encephalitis virus (vaccine strain, available from Kyoto biologies research institute, Inc.) were tested as follows:
mixing the above two viruses at a ratio of 1 × 104PFU dose intracranial inoculation 3 weeks old female BALB/c nude mice (purchased from Beijing Wintolite, Inc.), each virus inoculated in 8 mice, observed in 25 days of mice morbidity and mortality, 25 days after inoculation to the dose of mice mortality (death/inoculation number), the intracranial inoculation of mice survival curve. The results are shown in FIG. 1. In FIG. 1, ZIKV-LAV represents an attenuated strain of Zika virus, and JEV-LAV represents an Japanese encephalitis virus (vaccine strain). The results show that the attenuated strain of the Zika virus has lower toxicity than the Japanese encephalitis virus vaccine strain and good safety.
Example 2
This example illustrates the therapeutic effect of attenuated strains of Zika virus on glioma in a mouse model of human glioma.
1. Dividing female BALB/c nude mice of three weeks into two groups, injecting 50,000 glioma stem cells (GSCs, separated from human malignant glioma samples) capable of stably expressing firefly luciferase into each mouse of a control group; experimental groups each mouse was injected intracranial with 50,000 cells of the same species, simultaneously with 10,000PFU of an attenuated strain of ZIKV-LAV.
2. In vivo imaging experiments were performed 14, 21 and 28 days after intracranial injection to assess the growth of tumors in the brain by fluorescence values. The results are shown in FIG. 2. As can be seen from FIG. 2, the control mice had a tumor formation rate of 3/9, 8/9 and 8/9 at days 14, 21 and 28 after intracranial injection, respectively, and the fluorescence signals gradually increased, indicating that the tumor was growing rapidly. The tumor formation rates of the experimental mice at 14 days, 21 days and 28 days after intracranial injection are 0/10, 0/10 and 3/10 respectively, and the intracerebral fluorescence signals of the tumor-forming mice at 28 days are relatively small, which indicates that the tumor development of the experimental mice is slow.
3. And observing the survival state of the mouse, and drawing a survival curve of the mouse. The results are shown in FIG. 3. As can be seen from fig. 3, the survival time of the experimental group mice was much longer than that of the control group.
Example 3
This example illustrates the therapeutic effect of attenuated strains of Zika virus on glioma in a mouse model of human glioma.
Dividing female BALB/c nude mice with the age of three weeks into two groups, and injecting 50,000 glioma stem cells into each mouse in a control group in an intracranial manner; experimental groups each mouse was injected intracranial with 50,000 cells of the same species, simultaneously with 10,000PFU of an attenuated strain of ZIKV-LAV. On day 23 after intracranial injection, all mice were sacrificed to take brains, and H & E staining was performed after brain tissue was made into frozen sections to observe tumor size. The results are shown in FIG. 4. As can be seen from fig. 4, the tumors in the brains of the mice of the experimental group were much smaller than those of the control group.
According to the results, the invention can effectively treat the glioma by adopting the Zika virus attenuated strain, and prolong the survival time of the mouse.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (1)
1. Use of an attenuated strain of Zika virus having a deletion of a portion of nucleotides compared to wild-type Zika virus genomic RNA, wherein the deleted nucleotides are the nucleotides at position 10650-10659 in the wild-type Zika virus genomic RNA, for the preparation of a medicament for the treatment of glioma;
the wild Zika virus is the Zika virus with Genebank accession number KU 955593.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810076027.7A CN110075131B (en) | 2018-01-26 | 2018-01-26 | Application of Zika virus attenuated strain in treatment of brain glioma |
| PCT/CN2019/072763 WO2019144874A1 (en) | 2018-01-26 | 2019-01-23 | Application of zikv attenuated strain in treatment of brain glioma |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810076027.7A CN110075131B (en) | 2018-01-26 | 2018-01-26 | Application of Zika virus attenuated strain in treatment of brain glioma |
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| CN110075131A CN110075131A (en) | 2019-08-02 |
| CN110075131B true CN110075131B (en) | 2021-02-19 |
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| CN113679744B (en) * | 2020-05-18 | 2023-12-29 | 中国人民解放军军事科学院军事医学研究院 | Use of Zika virus or its use with drugs for immune checkpoint therapy in the treatment of glioblastoma |
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| EP3579869A4 (en) * | 2017-02-14 | 2020-10-21 | The Board of Regents of the University of Texas System | Live attenuated zika virus with 3'utr deletion, vaccine containing and use thereof |
| CN107188935B (en) * | 2017-07-20 | 2018-10-02 | 北京健乃喜生物技术有限公司 | A kind of zika virus NS1 antigenic mutants and its application |
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