CN110075131A - Application of the zika virus attenuated strain in treatment glioma - Google Patents
Application of the zika virus attenuated strain in treatment glioma Download PDFInfo
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- CN110075131A CN110075131A CN201810076027.7A CN201810076027A CN110075131A CN 110075131 A CN110075131 A CN 110075131A CN 201810076027 A CN201810076027 A CN 201810076027A CN 110075131 A CN110075131 A CN 110075131A
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Abstract
The present invention relates to therapeutic field of tumor, disclose application of the zika virus attenuated strain in treatment glioma.By using zika virus attenuated strain, the present invention can effectively treat glioma, and inhibit its development.
Description
Technical field
The present invention relates to therapeutic field of tumor, and in particular to application of the zika virus attenuated strain in treatment glioma.
Background technique
Neurogliocytoma (glioblastoma) is a kind of common height wellability primary brain tumors.Glioma
Patient survival is shorter, and High-grade Gliomas patient's median survival interval is only 1 year or so.Current glioma treatment scheme master
It to include operative treatment, radiotherapy and chemotherapy, but recurrence rate is very high after treatment, therapeutic effect is bad.Mainly
Reason first is that in glioma there is it is a small set of be referred to as glioma stem cells (glioma stem cells, GSCs)
Cell colony, this cell has the very strong ability for resisting radiotherapy and chemotherapy, and can be with self-renewing
And infinite multiplication, it is also assumed that being a group cell for determining glioma occurrence and development.Therefore, glioma stem cells are considered
It is a key target of glioma treatment.
Zika virus (zika virus, ZIKV) belongs to flaviviridae Flavivirus, and main includes African strain and Asia strain
Two types, zika virus Asia strain are proved related with fetus microcephaly recently.Main cause is that the strain can infect
The central nervous system of undeveloped mature, and main infection neural precursor therein (Neural precursor
Cells, NPCs), and eventually lead to such cell differentiation or death.But the Strain generally only results in slightly adult's infection
Clinical symptoms, such as short-term fever.Current research is concentrated mainly on the exploitation of zika virus vaccine, for zika virus sheet
The application of body, which still lacks, further to be illustrated.
Summary of the invention
It is of the existing technology the purpose of the invention is to overcome the problems, such as, a kind of zika virus attenuated strain is provided and is being treated
Application in glioma (glioblastoma).
To achieve the goals above, first aspect present invention provides zika virus attenuated strain in preparation for treating brain glue
Application in the drug of matter tumor, the zika virus attenuated strain have part core compared to wild type zika virus geneome RNA
The missing of thuja acid, wherein the nucleotide of missing, which includes at least, is located at 10650- in wild type zika virus geneome RNA
10659 nucleotide.
Second aspect of the present invention provides a kind of for treating the pharmaceutical composition of glioma, which contains
Zika virus attenuated strain and pharmaceutically acceptable auxiliary material.
Third aspect present invention provides the zika virus attenuated strain for treating glioma.
Fourth aspect present invention provides a kind of method for treating glioma, this method comprises: by a effective amount of stockaded village's card
Virus attenuation strain or a effective amount of aforementioned pharmaceutical compositions are administered to the subject with glioma.
By using zika virus attenuated strain, the present invention can effectively treat glioma, and inhibit its development.
Detailed description of the invention
Fig. 1 is the neurovirulence characteristic results of zika virus attenuated strain in embodiment 1；
Fig. 2 be embodiment 2 in zika virus attenuated strain on animal model to the treatment results of glioma (living body at
Picture)；
Fig. 3 be in embodiment 2 zika virus attenuated strain on animal model to the treatment results of glioma (when existence
Between)；
Fig. 4 is that the treatment results of glioma, (glioma is big on animal model for zika virus attenuated strain in embodiment 3
It is small).
Specific embodiment
The endpoint of disclosed range and any value are not limited to the accurate range or value herein, these ranges or
Value should be understood as comprising the value close to these ranges or value.For numberical range, between the endpoint value of each range, respectively
It can be combined with each other between the endpoint value of a range and individual point value, and individually between point value and obtain one or more
New numberical range, these numberical ranges should be considered as specific open herein.
On the one hand, the present invention provides zika virus attenuated strains to prepare answering in the drug for treating glioma
With the zika virus attenuated strain has the missing of partial nucleotide compared to wild type zika virus geneome RNA, wherein
The nucleotide of missing, which includes at least, is located in wild type zika virus geneome RNA 10650-10659 (3 ' noncoding region)
Nucleotide.
In the present invention, as long as there is the zika virus attenuated strain missing of above-mentioned nucleotide mesh of the invention can be realized
, in addition to this, any one in 10630-10674 in wild type zika virus geneome RNA nucleotide
Can also mutate (missing), it is preferred that in the case of, the zika virus only has above-mentioned ten nucleotide (10650-
10659) missing.The virus for constructing the partial nucleotide missing of geneome RNA is that those skilled in the art can be according to normal
What rule method carried out, thus details are not described herein again.
In the present invention, the wild type zika virus is preferably the zika virus that Genebank accession number is KU955593
(abbreviation KU955593).That is, according to the preferred embodiment of the present invention, the zika virus attenuated strain is KU955593 the
Attenuated strain obtained from 10650-10659 nucleotide deletions.
Above-mentioned zika virus attenuated strain can effectively inhibit the growth of glioma stem cells therefore to change an angle (in vitro)
For degree, the invention further relates to above-mentioned zika virus attenuated strains to inhibit the application in glioma stem cells in (in vitro).
On the other hand, the present invention also provides a kind of for treating the pharmaceutical composition of glioma, which is characterized in that should
Pharmaceutical composition contains zika virus attenuated strain and pharmaceutically acceptable auxiliary material, and the zika virus attenuated strain is compared to wild
Type zika virus geneome RNA has the missing of partial nucleotide, wherein the nucleotide of missing, which includes at least, is located at wild type stockaded village
10650-10659 nucleotide in card virus genome RNA.Detailed description about zika virus attenuated strain is not as before,
It repeats again, similarly hereinafter.The content of zika virus attenuated strain can be conventional selection in described pharmaceutical composition, for example, can be
104-5×104PFU/g。
Term " pharmaceutically acceptable " refers to not as biologically or not other aspects are unfavorable.Term
" auxiliary material " refers to being present in any substance in pharmaceutical preparation and non-active ingredient, including diluent, adhesive, lubrication
Agent, disintegrating agent, colorant, emulsifier, pH buffer and preservative etc..Auxiliary material used in the present invention can be various conventional use
In the auxiliary material of pharmacy.
According to the preferred embodiment of the present invention, described pharmaceutical composition, which further contains, is conducive to treat the brain colloid
The assistant medicament of tumor.The assistant medicament can be chemical drug, such as Temozolomide, elemene, or other are with above-mentioned
The medicament of curative effect.
In another aspect, the present invention provides the zika virus attenuated strains for treating glioma, which is characterized in that described
Zika virus attenuated strain has the missing of partial nucleotide compared to wild type zika virus geneome RNA, wherein the core of missing
Thuja acid includes at least the nucleotide positioned at 10650-10659 in wild type zika virus geneome RNA.
In addition, the present invention provides a kind of methods for treating glioma, which is characterized in that this method comprises: by effective
The zika virus attenuated strain of amount or a effective amount of foregoing pharmaceutical composition are administered to the subject with glioma, institute
State the missing that zika virus attenuated strain has partial nucleotide compared to wild type zika virus geneome RNA, wherein missing
Nucleotide includes at least the nucleotide positioned at 10650-10659 in wild type zika virus geneome RNA.Wherein, " effectively
Amount " refers to the effective dose that drug can play a role.
Above-mentioned subject can be the mammal of the common trouble glioma, especially primate (such as people
Or monkey) or rodent (such as mouse).
In the present invention, zika virus attenuated strain or pharmaceutical composition can be administered in a manner of any conventional, such as office
Portion's administration.Those skilled in the art can be attenuated according to the concrete mode of administration by zika virus attenuated strain or containing zika virus
The pharmaceutical composition of strain is prepared into different dosage forms.
The dosage of administration can be this field routine dosage (effective quantity), can according to various parameters, in particular according to by
Age, weight, gender and the health status of examination person determines.For example, for female, 3-4 week old, the BALB/c of weight 15-20g
The dosage of nude mice, zika virus attenuated strain every can be 1PFU/kg weight to 5 × 104PFU/kg weight (intracranial injection).
The present invention will be described in detail by way of examples below.
Experimental method used in following embodiments is conventional method unless otherwise specified.Institute in following embodiments
Material, reagent etc. can obtain from commercial channels unless otherwise specified.
Embodiment 1
The neurovirulence feature for the zika virus attenuated strain that the present embodiment is used to illustrate that the present invention uses.
Take zika virus attenuated strain (10650-10659 nucleotide deletions, referring to Chao Shan et al., A
live-attenuated Zika virus vaccine candidate induces sterilizing immunity in
Mouse models, Nature Medicine, 2017) and japanese encephalitis virus (vaccine strain is studied purchased from Chengdu biological products
Co., Ltd, institute) it is detected as follows:
By above two kinds of virus with 1 × 1043 week old female BAl BIc of dosage intercerebral inoculation/c nude mice of PFU (is tieed up purchased from Beijing
Company, tonneau China), 8 mouse of every kind of virus inoculation, mouse invasion and death condition in observation 25 days count after being inoculated with 25 days
The death rate (death toll/inoculation number) of the dosage group mouse draws intercerebral inoculation mouse survival curve.The result is shown in Figure 1.In Fig. 1,
ZIKV-LAV represents zika virus attenuated strain, and JEV-LAV represents japanese encephalitis virus (vaccine strain).The above results show stockaded village's card
The virulence of virus attenuation strain is lower than vaccine for virus of encephalitis B strain, has good safety.
Embodiment 2
The present embodiment is used to illustrate zika virus attenuated strain on human glioma mouse model to the treatment of glioma
Effect.
1. three week old female BAl BIcs/c nude mice is divided into two groups, every mouse intracranial of control group injects 50,000 can be steady
Surely the glioma stem cells of Fluc are expressed (GSCs is isolated from people's glioblastoma sample)；It is experimental group every small
50,000 allogenic cell of mouse intracranial injection, while 10 are given, the zika virus attenuated strain (ZIKV-LAV) of 000PFU.
2. it is swollen to assess intracerebral by fluorescent value for the progress living imaging experiment in the 14th, 21 and 28 day after intracranial injection
The upgrowth situation of tumor.As a result see Fig. 2.Figure it is seen that control group mice tumor formation in the 14th, 21 and 28 day after intracranial injection
Rate is respectively 3/9,8/9 and 8/9, and fluorescence signal gradually increases, and shows that tumour is mushrooming out.And experimental mice is in cranium
The the 14th, 21 and 28 day tumor formation rate is respectively 0/10,0/10 and 3/10 after interior injection, and glimmering in tumor formation mouse brain at the 28th day
Optical signal is relatively small, shows that experimental mice tumor development is slow.
3. observing mouse survival state, mouse survival curve is drawn.As a result see Fig. 3.From figure 3, it can be seen that experimental group is small
The life span of mouse is longer than control group.
Embodiment 3
The present embodiment is used to illustrate zika virus attenuated strain on human glioma mouse model to the treatment of glioma
Effect.
Three week old female BAl BIcs/c nude mice is divided into two groups, it is dry that every mouse intracranial of control group injects 50,000 glioma
Cell；Every mouse intracranial of experimental group injects 50,000 allogenic cell, while giving 10, the zika virus attenuated strain of 000PFU
(ZIKV-LAV).The 23rd day after intracranial injection, all mouse execution carry out H&E after taking brain, brain tissue that frozen section is made
Tumor size is observed in dyeing.As a result see Fig. 4.From fig. 4, it can be seen that the tumour in experimental mice brain is much smaller than control group.
By the above results as can be seen that the present invention can effectively treat brain colloid by using zika virus attenuated strain
Tumor extends the life span of mouse.
The preferred embodiment of the present invention has been described above in detail, and still, the present invention is not limited thereto.In skill of the invention
In art conception range, can with various simple variants of the technical solution of the present invention are made, including each technical characteristic with it is any its
Its suitable method is combined, and it should also be regarded as the disclosure of the present invention for these simple variants and combination, is belonged to
Protection scope of the present invention.
Claims (6)
1. zika virus attenuated strain is preparing the application in the drug for treating glioma, the zika virus attenuated strain phase
Than having the missing of partial nucleotide in wild type zika virus geneome RNA, wherein the nucleotide of missing, which includes at least, to be located at
10650-10659 nucleotide in wild type zika virus geneome RNA.
2. application according to claim 1, wherein the wild type zika virus is that Genebank accession number is
The zika virus of KU955593.
3. a kind of for treating the pharmaceutical composition of glioma, which is characterized in that the pharmaceutical composition contains zika virus and subtracts
Strain and pharmaceutically acceptable auxiliary material, the zika virus attenuated strain have compared to wild type zika virus geneome RNA
The missing of partial nucleotide, wherein the nucleotide of missing, which includes at least, to be located at the in wild type zika virus geneome RNA
10650-10659 nucleotide.
4. pharmaceutical composition according to claim 3 is further conducive to the adjuvant for treating the glioma
Agent.
5. the zika virus attenuated strain for treating glioma, which is characterized in that the zika virus attenuated strain is compared to open country
Raw type zika virus geneome RNA has the missing of partial nucleotide, wherein the nucleotide of missing, which includes at least, is located at wild type
10650-10659 nucleotide in zika virus geneome RNA.
6. a kind of method for treating glioma, which is characterized in that this method comprises: by a effective amount of zika virus attenuated strain or
Pharmaceutical composition described in a effective amount of claim 3 or 4 is administered to the subject with glioma, and the zika virus subtracts
Strain has the missing of partial nucleotide compared to wild type zika virus geneome RNA, wherein the nucleotide of missing at least wraps
Include the nucleotide positioned at 10650-10659 in wild type zika virus geneome RNA.
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 |
Applications Claiming Priority (1)
| 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 |
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| CN110075131A true CN110075131A (en) | 2019-08-02 |
| CN110075131B CN110075131B (en) | 2021-02-19 |
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| CN201810076027.7A Active CN110075131B (en) | 2018-01-26 | 2018-01-26 | Application of Zika virus attenuated strain in treatment of brain glioma |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113679744A (en) * | 2020-05-18 | 2021-11-23 | 中国人民解放军军事科学院军事医学研究院 | Application of Zika virus strain in treating glioblastoma |
Citations (2)
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| CN107188935A (en) * | 2017-07-20 | 2017-09-22 | 北京健乃喜生物技术有限公司 | A kind of zika virus NS1 antigenic mutants and its application |
| CN110381993A (en) * | 2017-02-14 | 2019-10-25 | 得克萨斯大学体系董事会 | Attenuation zika virus living with 3 ' UTR missing, vaccine containing the virus and application thereof |
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2018
- 2018-01-26 CN CN201810076027.7A patent/CN110075131B/en active Active
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2019
- 2019-01-23 WO PCT/CN2019/072763 patent/WO2019144874A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110381993A (en) * | 2017-02-14 | 2019-10-25 | 得克萨斯大学体系董事会 | Attenuation zika virus living with 3 ' UTR missing, vaccine containing the virus and application thereof |
| CN107188935A (en) * | 2017-07-20 | 2017-09-22 | 北京健乃喜生物技术有限公司 | A kind of zika virus NS1 antigenic mutants and its application |
Non-Patent Citations (2)
| Title |
|---|
| SHAN C等: "A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models", 《NATURE MEDCINE》 * |
| ZHU Z等: "Zika virus has oncolytic activity against glioblastoma stem cells", 《THE JOURNAL OF EXPERIMENTAL MEDICINE》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113679744A (en) * | 2020-05-18 | 2021-11-23 | 中国人民解放军军事科学院军事医学研究院 | Application of Zika virus strain in treating glioblastoma |
| 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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| Publication number | Publication date |
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| WO2019144874A1 (en) | 2019-08-01 |
| CN110075131B (en) | 2021-02-19 |
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