WO2009052737A1 - Médicament destiné à la prévention et au contrôle de la maladie d'alzheimer - Google Patents

Médicament destiné à la prévention et au contrôle de la maladie d'alzheimer Download PDF

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WO2009052737A1
WO2009052737A1 PCT/CN2008/072676 CN2008072676W WO2009052737A1 WO 2009052737 A1 WO2009052737 A1 WO 2009052737A1 CN 2008072676 W CN2008072676 W CN 2008072676W WO 2009052737 A1 WO2009052737 A1 WO 2009052737A1
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PCT/CN2008/072676
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Yanjiang Wang
Xinfu Zhou
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Yanjiang Wang
Xinfu Zhou
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • 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
    • A61K35/761—Adenovirus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
    • C12N2710/10332—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
    • C12N2710/10341—Use of virus, viral particle or viral elements as a vector
    • C12N2710/10343—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the invention relates to the field of biomedicine, in particular to a medicament for the prevention and treatment of Alzheimer's disease.
  • AD Alzheimer's disease
  • AD is a progressive neurodegenerative disease characterized by dementia and is an important disease that currently threatens the health and life of the elderly.
  • AD patients There are about 24.3 million AD patients worldwide, and the number of new cases is 4.6 million per year. It is estimated that there will be 81 million AD patients worldwide by 2040.
  • AD has become the 7th to 8th cause of death in the current population, and the 4th to 5th cause of death in people over 65 years of age.
  • the economic burden of AD on families and society ranks third among all diseases, second only to heart disease and cancer. China is facing a severe population aging situation and is the country with the largest number of elderly people in the world.
  • AD will become a very heavy economic and social burden for China.
  • AD Alzheimer's disease
  • ⁇ is considered to be a pathogenic substance of AD, and lowering ⁇ level in the brain is an important strategy for prevention and treatment of AD.
  • Immunotherapy is an important advance in recent years. Studies have shown that active immunization (inoculated with ⁇ vaccine) and passive immunization (direct injection of anti- ⁇ antibody) can effectively eliminate ⁇ in AD mice and patients, reduce ⁇ -related pathological changes, and improve cognitive ability. Therefore, anti- ⁇ immunotherapy is considered to be the most promising new method for the treatment of AD in patients with brain ⁇ . However, immunotherapy has some serious side effects, including causing central nervous system inflammation and microvascular out Blood. These side effects are associated with the Fc-segment-mediated immune inflammatory response of anti-A ⁇ antibodies. (3), the content of the invention
  • the object of the present invention is to provide a medicament for preventing and treating Alzheimer's disease, which can carry the scFv gene in a long-term production in the human body, and can continuously remove the ⁇ in the brain while avoiding the central nervous system inflammatory reaction and Side effects of microvascular bleeding.
  • the object of the present invention is achieved by the technical scheme of linking a front end of one, two or more anti- ⁇ ⁇ single-chain antibody genes to a secretion signal peptide by using a recombinant virus for gene transfection as a vector.
  • a nucleotide sequence which is then inserted into a gene of a recombinant virus and packaged into a product by a recombinant virus; wherein the nucleotide sequence of the anti- ⁇ single-chain antibody gene is:
  • Trp Met Gly Trp l ie Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gin
  • the recombinant virus may be a recombinant adeno-associated virus, which may be a lentivirus, an adenovirus, or a retrovirus.
  • the secretory signal peptide nucleotide sequence can be: atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactcc, which can be: gagcccacag cctcttctg aggatcctgg agcaggtggc atgccactcc gactgga , or tacaggctcc gaggagccct ccggtcaggat ggatgacagc cttcgctt atggacc , of course, it can be any protein that can be expressed A nucleotide sequence that is secreted outside the cell.
  • scFv It is a human-derived anti- ⁇ single-chain antibody. Its English word is Single chain antibody, usually abbreviated as scFv.
  • pGEX-6P-scFv This is a plasmid containing the scFv gene (named pGEX-6P) for expression of the scFv protein.
  • AAV It is an adeno-associated virus, and its English word is Adeno-associated vims, usually abbreviated to AAV.
  • pSNAVl This is a plasmid encoding the AAV gene for the production of AAV.
  • pSNAV1-scFv This is an AAV plasmid containing the scFv gene for producing AAV containing the scFv gene.
  • BHK-21 cells It is a cell used to produce AAV.
  • G418 It is an antibiotic used to select cells containing the pSNAV1-scFv plasmid.
  • AAV rep gene It is a gene encoding AAV re. rep is an abbreviation of replica, which plays an important role in viral replication, gene expression regulation and integration.
  • AAV cap gene It is a gene encoding AAV cap, and cap is an abbreviation for capsid, which plays an important role in viral packaging.
  • Helper virus rHSVl/repcap It is a helper virus containing the AAV rep gene and the cap gene. pSNAV1 requires the help of the helper virus rHSVl/repcap to produce AAV.
  • rAAV virus particle It is a recombinant adeno-associated virus, and its English word is recombined adeno-associated virus. In this patent, it refers to AAV encoded by pSNAV1.
  • AAV-scFv It refers to AAV containing the scFv gene.
  • the recombinant virus is: AAV
  • the signal peptide sequence is: atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactcc as an example to illustrate the preparation method and use method of the present invention:
  • the preparation method of the present invention is: First, a polymerase chain reaction (PCR) method is employed.
  • the scFv gene was cloned from the pGEX-6P-scFv plasmid, and a secretion signal peptide and a restriction site were introduced, and then ligated into the AAV plasmid pSNAV1 to construct a pSNAV1-scFv plasmid.
  • the signal peptide sequence ⁇ Ll is: atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactcc.
  • the resulting plasmid was transformed and amplified.
  • the plasmid was extracted and identified by one-way DNA sequencing.
  • the pSNAV1-scFv plasmid was introduced into BHK-21 cells, and the pSNAV1-scFv plasmid vector cells were selected by G418.
  • the helper virus rHSVl/repcap containing the AAV rep and cap genes was added to infect the pSNAV1-scFv vector cells for virus replication and packaging. Collect the culture supernatant and centrifuge. Polyethylene glycol and NaCl were added, incubated, centrifuged, and rAAV virus particle pellets were collected. Resuspend in PBS and extract with chloroform. The supernatant was collected, and the AAV virus particles were purified by ion exchange column chromatography. The purity of the AAV-scFv virus was identified by SDS gel electrophoresis, and the virus titer was determined by DNA dot blot hybridization. Store at low temperature after dispensing.
  • the method of use of the present invention is to inject the AAV-scFv virus preparation into a brain tissue, a lateral ventricle or muscle tissue with a syringe, and the AAV-scFv virus infects tissue cells, and carries the carried scFv gene into the cells.
  • the scFv gene is expressed in cells, produces scFv, and is released to the outside of the cell, and binds to ⁇ to exert a therapeutic effect of clearing ⁇ in the brain.
  • scFv has ⁇ binding ability, can inhibit the polymerization of ⁇ monomer, and promote the depolymerization of ⁇ fibrils.
  • the scFv contains no Fc segments and avoids the side effects associated with it.
  • the scFv gene is transfected into the periphery and brain by the recombinant virus for gene transfection, and the scFv gene is expressed and released in the cell, thereby achieving the purpose of clearing the ⁇ in the brain and treating AD. Since the above technical solution is adopted, the present invention has the following advantages:
  • scFv is expressed in vivo for a long time, avoiding repeated administration of anti-A ⁇ drugs, which can reduce the cost of treatment.
  • the invention provides a safe and effective and long-term function of AD treatment, and has broad clinical application prospects.
  • Figure 1 is a graphical representation of the comparison of the fluorescence intensity of ⁇ 42 fibers after incubation with ⁇ 42 monomer alone or with seFv GST or GST;
  • Figure 2 is a schematic diagram showing the comparison of the fluorescence intensity of ⁇ 42 fiber after ⁇ 42 fiber alone or in combination with seFv GST or GST;
  • Figure 3 is a photograph showing the scavenging effect of AAV scFv hippocampal transfection on A ⁇ .
  • the present invention uses a recombinant virus for gene transfection as a vector, and connects the front end of one, two or more anti- ⁇ single-chain antibody genes to a secretory signal peptide nucleotide sequence, and then the anti- ⁇ single-strand
  • the antibody gene is inserted into the gene of the recombinant virus and packaged into a product by the recombinant virus; wherein the nucleotide sequence of the anti- ⁇ single-chain antibody gene is:
  • Trp Met Gly Trp l ie Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gin
  • the recombinant virus may be a recombinant adeno-associated virus, which may be a lentivirus, an adenovirus, or a retrovirus.
  • the secretory signal peptide nucleotide sequence can be: atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactcc, which can be: gagcccacag cctcttctg aggatcctgg agcaggtggc atgccactcc gactgga , or it can be: tacaggctcc gaggagccct ccggtcaggat ggatgacagc cttcgcctt atggacc , of course, it can be anything else that has the same effect and Functional secretion signal peptide nucleotide sequence.
  • the recombinant virus is: AAV
  • the signal peptide sequence is: atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactcc as an example to illustrate the preparation method and use method of the present invention:
  • the preparation method of the present invention is: First, a polymerase chain reaction (PCR) method is employed.
  • PCR polymerase chain reaction
  • the scFv gene was cloned from the pGEX-6P-scFv plasmid and introduced into the secretion signal peptide and the cleavage site.
  • the restriction enzyme was digested into the AAV plasmid pSNAV1 to construct a pSNAV1-scFv plasmid.
  • the signal peptide sequence ⁇ Ll is: atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactcc.
  • the resulting plasmid was transformed and amplified.
  • the plasmid was extracted and identified by one-way DNA sequencing.
  • the pSNAV1-scFv plasmid was introduced into BHK-21 cells, and the pSNAV1-scFv plasmid vector cells were selected by G418.
  • helper virus rHSV1/repcap containing the AAV rep and cap genes was added, and the pSNAV1-scFv vector cells were infected to carry out virus replication and packaging. Collect the culture supernatant and centrifuge. Polyethylene glycol and NaCl were added, incubated, and centrifuged to collect rAAV virus particle pellets. Resuspend in PBS and extract with chloroform. The supernatant was collected, and the AAV virus particles were purified by ion exchange column chromatography. The purity of AAV-scFv virus was identified by SDS gel electrophoresis, and the virus titer was determined by DNA dot blot hybridization. Store at low temperature after dispensing.
  • the method of use of the present invention is to inject the AAV-scFv virus preparation into a brain tissue, a lateral ventricle or muscle tissue with a syringe, and the AAV-scFv virus infects tissue cells, and carries the carried scFv gene into the cells.
  • the scFv gene is expressed in cells, produces scFv, and is released to the outside of the cell, and binds to ⁇ to exert a therapeutic effect of clearing ⁇ in the brain.
  • the scFv has an ⁇ binding ability, which inhibits the polymerization of ⁇ monomers and promotes the depolymerization of ⁇ fibrils.
  • the scFv contains no Fc segments to avoid side effects associated with it.
  • the scFv gene is transfected into the periphery and brain by the recombinant virus for gene transfection, and the scFv gene is expressed and released in the cell, thereby achieving the purpose of eliminating ⁇ in the brain and treating AD.
  • ⁇ refers to the ⁇ 42 monomer alone incubation group
  • ⁇ +scFv refers to ⁇ 42 monomer and seFv-GST protein co-incubation group
  • ⁇ +GST refers to ⁇ 42 monomer and GST protein co-incubation group
  • GST refers to GST protein alone incubation group . It can be seen from Fig. 1 that there is no significant difference in the fluorescence intensity between the ⁇ 42 alone culture group and the ⁇ 42 and GST protein co-incubation group in the positive control group in this experiment, indicating that the fluorescence intensity of ⁇ 42 polymer in the ⁇ 42 and scFv-GST co-incubation group is decreased.
  • ⁇ refers to the ⁇ 42 fiber alone incubation group
  • ⁇ +scFv refers to ⁇ 42 fiber co-incubation with scFv GST protein.
  • ⁇ +GST refers to the ⁇ 42 fiber co-incubation group with GST protein
  • GST refers to the GST protein alone incubation group.
  • the present invention employs a 9-month-old Mo/Hu APPswe PSldE9 AD mouse.
  • the mouse is a double transgenic mouse carrying a chimeric gene of the Presenilin-1 DeltaE9 mutant and the human APP Swedish mutant (APPSwe, KM 593/594 NL).
  • mice After anesthesia in mice, 2 ⁇ of AAV-scFv virus (3 ⁇ 10 12 particles/ml) was injected into the left hippocampus, and 2 ⁇ of normal saline was injected into the right hippocampus. In the control group, 2 ⁇ of AAV-EGFP (3 ⁇ 10 12 particles/ml) was injected into the left hippocampus, and 2 ⁇ of normal saline was injected into the right hippocampus. After 1 month, brain tissue was taken for analysis, and photographs as shown in Fig. 3 were taken, respectively. In Fig.
  • ⁇ is the control group's total ⁇ plaque staining (immunohistochemical staining): ⁇ is the control ⁇ dense plaque staining (Thioflavine) S staining); C is the total ⁇ plaque staining (immunohistochemical staining) of AAV ⁇ scFv hippocampal injection group; D is ⁇ dense plaque staining (Thioflavme S staining) of AAV ⁇ scFv hippocampal injection group. It can be seen from Fig. 3 that in the control group, the number of immunohistochemical ⁇ plaques on the injection side, the average size, and the percentage of total plaques in total hippocampus were not significantly different from those on the control side, as shown in Fig.
  • the ratio of the injection side to the control side was used to compare between the AAV-scFv hippocampal injection group and the control group.
  • Number, average size and size of immunohistochemically reactive ⁇ plaques in the AAV-scFv injection group The percentage of total area of hippocampus in all plaques was significantly lower than that in the control group, as shown in Table 1.
  • the number of ⁇ plaques and the total area of hippocampus in the AAV-scFv injection group was lower than that of the control side.
  • the difference in size was not statistically significant, as shown in Table 2.
  • scFv does not activate microglia and T lymphocytes in the brain, nor does it cause microvascular bleeding in the brain.

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Abstract

Un médicament destiné à la prévention et au traitement de la maladie d'Alzheimer est caractérisé en ce qu'un virus recombinant dédié à la transfection de gènes est considéré comme un vecteur; l'extrémité avant d'un, deux ou d'une pluralité de gènes d'anticorps à chaîne unique anti-Aβ est liée, respectivement, à une séquence d'ADN de peptide signal de sécrétion; et ensuite les gènes d'anticorps à chaîne unique anti-Aβ sont insérés dans le génome du virus recombinant; finalement, un produit encapsidé est formé par l'intermédiaire du virus recombinant. L'invention concerne la production d'un anticorps à chaîne unique anti-Aβ dans le corps par transfection des gènes d'anticorps à chaîne unique anti-Aβ capables de prohiber l'isomérisation des monomères d'Aβ et de favoriser la dépolymérisation des polymères d'Aβ sur la périphérie et dans le cerveau, de manière à exprimer le scFv dans le corps pendant une longue période, afin d'éliminer efficacement l'Aβ dans le cerveau touché par la maladie d'Alzheimer, de prévenir la réaction inflammatoire du système nerveux central et l'effet secondaire de saignement des capillaires produit dans l'immunothérapie anti-Aβ, d'éviter un apport répété du médicament anti-Aβ et de réduire le coût du traitement. L'invention concerne une nouvelle technologie sans risque et efficace de traitement de la maladie d'Alzheimer qui présente une longue période d'action et une large perspective d'applications cliniques.
PCT/CN2008/072676 2007-10-15 2008-10-14 Médicament destiné à la prévention et au contrôle de la maladie d'alzheimer WO2009052737A1 (fr)

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