WO2019144874A1 - Application d'une souche atténuée de virus zika (zikv) dans le traitement d'un gliome cérébral - Google Patents

Application d'une souche atténuée de virus zika (zikv) dans le traitement d'un gliome cérébral Download PDF

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Publication number
WO2019144874A1
WO2019144874A1 PCT/CN2019/072763 CN2019072763W WO2019144874A1 WO 2019144874 A1 WO2019144874 A1 WO 2019144874A1 CN 2019072763 W CN2019072763 W CN 2019072763W WO 2019144874 A1 WO2019144874 A1 WO 2019144874A1
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Prior art keywords
zika virus
attenuated
attenuated strain
glioma
wild
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PCT/CN2019/072763
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English (en)
Chinese (zh)
Inventor
秦成峰
满江红
史佩勇
陈奇
吴瑾
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中国人民解放军军事科学院军事医学研究院
史佩勇
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Application filed by 中国人民解放军军事科学院军事医学研究院, 史佩勇 filed Critical 中国人民解放军军事科学院军事医学研究院
Publication of WO2019144874A1 publication Critical patent/WO2019144874A1/fr

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    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of tumor treatment, in particular to the application of an attenuated strain of Zika virus in treating glioma.
  • Glioblastoma is a common highly invasive primary brain tumor.
  • the survival time of patients with glioma is short, and the median survival of patients with high-grade glioma is only about 1 year.
  • Current glioma treatment programs mainly include surgery, radiation therapy and chemical therapy, but the recurrence rate is high after treatment and the treatment effect is not good.
  • GSCs glioma stem cells
  • Zika virus belongs to the genus Flavivirus of the Flaviviridae family, mainly including African strains and Asian strains.
  • the Zika virus Asian strain has recently been confirmed 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), and eventually cause such cells to differentiate or die.
  • NPCs neural precursor cells
  • the virus strain generally causes only mild clinical symptoms such as short-term fever.
  • the current research is mainly focused on the development of Zika virus vaccine, and there is still no further clarification on the application of Zika virus itself.
  • the object of the present invention is to overcome the problems of the prior art and to provide an application of a Zika virus attenuated strain in the treatment of gliomas.
  • a first aspect of the present invention provides an application of an attenuated strain of Zika virus in the preparation of a medicament for treating glioma, wherein the Zika virus attenuated strain is compared to a wild-type Zika virus genome
  • the RNA has a partial nucleotide deletion, wherein the deleted nucleotide includes at least nucleotides located at positions 10650-10659 in the wild type Zika virus genomic RNA.
  • a second aspect of the invention provides a pharmaceutical composition for treating glioma, the pharmaceutical composition comprising an attenuated strain of Zika virus and a pharmaceutically acceptable adjuvant.
  • a third aspect of the invention provides an attenuated strain of Zika virus for treating glioma.
  • a fourth aspect of the invention provides a method of treating a glioma, 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 glioma Tester.
  • the present invention is effective in treating glioma and inhibiting its development.
  • Example 1 is a result of the neurotoxicity characteristic of the attenuated strain of Zika virus in Example 1;
  • Example 2 is a result of treatment of glioma in an animal model (in vivo imaging) of an attenuated strain of Zika virus in Example 2;
  • Figure 3 is a graph showing the treatment results (lifetime) of glial attenuated strain of Zika virus in animal model on glioma in Example 2;
  • Figure 4 is a graph showing the treatment results (glioma size) of gliomas in an animal model in an attenuated strain of Zika virus in Example 3.
  • the present invention provides the use of an attenuated strain of Zika virus in the preparation of a medicament for treating glioma, wherein the Zika virus attenuated strain has a partial nucleoside compared to the wild-type Zika virus genomic RNA.
  • the object of the present invention can be achieved as long as the attenuated strain of Zika virus has the above-mentioned nucleotide deletion, in addition to the nucleoside of the 10630-10674 located in the wild type Zika virus genome RNA.
  • Mutation can also occur in any of the acids, but preferably, the Zika virus has only the deletion of the above ten nucleotides (positions 10650-10659).
  • the construction of a partial nucleotide-deleted virus of genomic RNA can be carried out by a person skilled in the art according to a conventional method, and thus will not be described herein.
  • the wild type Zika virus is preferably Zika virus (KU955593) with Genebank accession number KU955593. That is, according to a preferred embodiment of the present invention, the attenuated Zika virus strain is an attenuated strain obtained by deleting nucleotides at positions 10650-10659 of KU955593.
  • the above-mentioned attenuated strain of Zika virus can effectively (in vitro) inhibit the growth of glioma stem cells, and therefore, in other respects, the present invention also relates to the above-mentioned attenuated Zika virus in inhibiting glioma stem cells (in vitro) Applications.
  • the present invention provides a pharmaceutical composition for treating glioma, characterized in that the pharmaceutical composition comprises an attenuated strain of Zika virus and a pharmaceutically acceptable excipient, said Zika
  • the attenuated strain of the virus has a partial nucleotide deletion compared to the wild-type Zika virus genomic RNA, wherein the deleted nucleotide comprises at least nucleotides located at positions 10650-10659 in the wild-type Zika virus genome RNA.
  • the detailed description of the attenuated strain of Zika virus is as described above, and will not be described again.
  • the content of the Zika virus attenuated strain in the pharmaceutical composition may be a conventional selection, and may be, for example, 10 4 - 5 ⁇ 10 4 PFU / g.
  • auxiliary refers to any substance that is not present as an active ingredient in a pharmaceutical formulation, including diluents, binders, lubricants, disintegrants, colorants, emulsifiers, pH buffers, preservatives, and the like.
  • the excipients used in the present invention may be various conventional excipients for pharmaceutical use.
  • the pharmaceutical composition further comprises an auxiliary agent which is useful for treating the glioma.
  • the auxiliary agent may be a chemical, such as temozolomide, elemene, or the like, or other agents having the above therapeutic effects.
  • the present invention provides an attenuated Zika virus strain for treating glioma, characterized in that the Zika virus attenuated strain has a partial nucleotide compared to the wild-type Zika virus genomic RNA.
  • the deletion, wherein the deleted nucleotide comprises at least nucleotides located at positions 10650-10659 in the wild-type Zika virus genomic RNA.
  • the present invention provides a method of treating glioma, comprising: administering an effective amount of an attenuated strain of Zika virus or an effective amount of the pharmaceutical composition as described above to the patient
  • the Zika virus attenuated strain has a partial nucleotide deletion compared to the wild-type Zika virus genomic RNA, wherein the deleted nucleotide includes at least a wild type Zika Nucleotides at positions 10650-10659 in viral genomic RNA.
  • "effective amount” refers to an effective dose at which a drug can function.
  • the subject may be a common mammal having the glioma, particularly a primate (such as a human or a monkey) or a rodent (such as a mouse).
  • a primate such as a human or a monkey
  • a rodent such as a mouse
  • the Zika virus attenuated strain or the pharmaceutical composition can be administered in any conventional manner, such as topical administration.
  • One skilled in the art can prepare attenuated Zika virus strains or pharmaceutical compositions containing Zika virus attenuated strains into different dosage forms depending on the particular mode of administration.
  • the dose administered can be a conventionally effective dose (effective amount) in the art and can be determined according to various parameters, particularly depending on the age, weight, sex and health of the subject. For example, for females, BALB/c nude mice, 3-4 weeks old, weighing 15-20 g, attenuated Zika virus can be used at a dose of 1 PFU/kg body weight to 5 ⁇ 10 4 PFU/kg body weight (intracranial injection).
  • This example is intended to illustrate the neurovirulence characteristics of the attenuated Zika virus strain used in the present invention.
  • Attenuated Zika virus strain (nucleotide deletion at 10650-10659, see Chao Shan et al., A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models, Nature Medicine, 2017) and Japanese encephalitis
  • the virus (vaccine strain, purchased from Chengdu Biological Products Research Institute Co., Ltd.) was tested as follows:
  • the above two viruses were intracranially inoculated with 3 weeks old female BALB/c nude mice (purchased from Beijing Vital Lihua Company) at a dose of 1 ⁇ 10 4 PFU, 8 mice per virus were inoculated, and observed for 25 days. Mortality and mortality of the rats, the mortality (number of deaths/vaccination) of the mice in the dose group was counted 25 days after the inoculation, and the survival curve of the intracranial inoculated mice was drawn.
  • the results are shown in Figure 1.
  • ZIKV-LAV represents an attenuated strain of Zika virus
  • JEV-LAV represents a Japanese encephalitis virus (vaccine strain).
  • the above results indicate that the attenuated strain of Zika virus is less toxic than the Japanese encephalitis virus vaccine strain and has good safety.
  • This example is used to illustrate the therapeutic effect of Zika virus attenuated strain on glioma in a mouse model of human glioma.
  • mice Three-week-old female BALB/c nude mice were divided into two groups. Each mouse in the control group was intracranially injected with 50,000 glioma stem cells (GSCs) stably expressing firefly luciferase (isolated from human malignant colloid). Tumor samples); each mouse in the experimental group was intracranially injected with 50,000 cells of the same type, and 10,000 PFU of Zika virus attenuated strain (ZIKV-LAV) was administered at the same time.
  • GSCs glioma stem cells
  • ZIKV-LAV Zika virus attenuated strain
  • This example is used to illustrate the therapeutic effect of Zika virus attenuated strain on glioma in a mouse model of human glioma.
  • mice Three-week-old female BALB/c nude mice were divided into two groups. Each mouse in the control group was intracranially injected with 50,000 glioma stem cells. Each mouse in the experimental group was intracranially injected with 50,000 cells of the same type, and 10,000 PFU was administered at the same time. Attenuated Zika virus (ZIKV-LAV). On the 23rd day after the intracranial injection, all the mice were sacrificed and the brain tissues were made into frozen sections, and then H&E staining was performed to observe the tumor size. The results are shown in Figure 4. As can be seen from Figure 4, the tumors in the brain of the experimental group were much smaller than those in the control group.
  • ZIKV-LAV Attenuated Zika virus
  • the present invention can effectively treat glioma by prolonging the survival time of mice by using the Zika virus attenuated strain.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne le domaine du traitement de tumeurs et concerne une application d'une souche atténuée de ZIKV dans le traitement d'un gliome cérébral. Selon la présente invention, l'utilisation d'une souche atténuée de ZIKV peut traiter efficacement un gliome cérébral et inhiber son développement.
PCT/CN2019/072763 2018-01-26 2019-01-23 Application d'une souche atténuée de virus zika (zikv) dans le traitement d'un gliome cérébral WO2019144874A1 (fr)

Applications Claiming Priority (2)

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CN201810076027.7 2018-01-26
CN201810076027.7A CN110075131B (zh) 2018-01-26 2018-01-26 寨卡病毒减毒株在治疗脑胶质瘤中的应用

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CN113679744B (zh) * 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 寨卡病毒或其与用于免疫检查点治疗的药物在治疗胶质母细胞瘤中的用途

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EP3579869A4 (fr) * 2017-02-14 2020-10-21 The Board of Regents of the University of Texas System Virus zika vivant atténué avec délétion de 3'utr, vaccin le contenant et utilisation de celui-ci
CN107188935B (zh) * 2017-07-20 2018-10-02 北京健乃喜生物技术有限公司 一种寨卡病毒ns1抗原突变体及其应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEN, QI ET AL.: "Treatment of Human Glioblastoma with A Live Attenuated Zika Virus Vaccine Candidate", HOST-MICROBE BIOLOGY, vol. 9, no. 5, 18 September 2018 (2018-09-18), pages 1 - 13, XP055627648 *
SHAN, CHAO ET AL.: "A Live-attenuated Zika Virus Vaccine Candidate Induces Sterilizing Immunity in Mouse Models", NATURE MEDICINE, vol. 23, no. 6, 10 April 2017 (2017-04-10), pages 763 - 767, XP055539486, doi:10.1038/nm.4322 *
Z HU, ZHE ET AL.: "Zika Virus has Oncolytic Activity Against Glioblastoma Stem Cells", J. EXP. MED, vol. 214, no. 10, 5 September 2017 (2017-09-05), pages 2843 - 2857, XP055436428, doi:10.1084/jem.20171093 *

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