WO2010114143A1 - Système pour augmenter l'activité de promoteur spécifique, et vecteur portant le système - Google Patents

Système pour augmenter l'activité de promoteur spécifique, et vecteur portant le système Download PDF

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WO2010114143A1
WO2010114143A1 PCT/JP2010/056117 JP2010056117W WO2010114143A1 WO 2010114143 A1 WO2010114143 A1 WO 2010114143A1 JP 2010056117 W JP2010056117 W JP 2010056117W WO 2010114143 A1 WO2010114143 A1 WO 2010114143A1
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promoter
seq
dna
specific
gene
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Japanese (ja)
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公文裕巳
柏倉祐司
渡部昌実
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国立大学法人岡山大学
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • LNCap cells androgen-dependent prostate cancer
  • X-SCID gene therapy for humans with retrovirus induces leukemia
  • OTC ornithine transcarbamylase
  • adenoviral vectors are introduced into the hepatic vein. It was injected to cause gene expression in hepatocytes, but there was a problem that it caused severe liver failure and resulted in death.
  • Specific promoters include NkX2.5 promoter, GATA4 promoter, MLC (myosin light chain) 2v promoter, cardiac ankyrin repeat promoter, ANF promoter, BNP (brain native factor) promoter, ANP (attrint promoter) 1 promoter, tubulin ⁇ 1 promoter, SCG10 promoter, GFAP promoter, calcium / calmodulin-dependent protein kinase II promoter, neuron-specific enolase promoter, platelet-derived low factor beta (PDGF- ⁇ ) chain promoter, hTERT promoter, prostate specific antigen (PSA) promoter, carcinoembryonic antigen (CEA) promoter, ⁇ -fetoprotein (AFP) promoter, cyclooxygenase-2 (
  • the therapeutic gene is a tumor suppressor gene that can be used for tumor therapy.
  • the tumor suppressor gene is a REIC / Dkk-3 gene.
  • [12] A disease detection or treatment preparation comprising the vector according to any one of [7] to [11].
  • DNA encoding GAL4 DNA-binding domain, DNA encoding glucocorticoid receptor (GR) inserted with DNA encoding polyglutamine (Poly Q) or polyproline (PolyP), and transcriptional activation domain of VP16 A DNA construct comprising a DNA sequence encoding a transcription factor consisting of DNA fused in this order.
  • FIG. 1 is a diagram showing an outline of the improved TSTA system of the present invention.
  • FIG. 1A shows a structure of a structure used for a conventional single step transcription system
  • FIG. 1B shows a structure of a structure used for a conventional two amplification system
  • FIG. The structure of is shown.
  • FIG. 2 is a diagram showing the structure of the adeno-associated virus vector of the present invention.
  • FIG. 2A shows a structural diagram of an expression cassette (AdTSTA / RGD-AAV-Luc), which is a DNA construct introduced into an adeno-associated virus vector containing hTERT as a specific promoter and luciferase gene as a specific gene.
  • FIG. 4 is a view showing primer sequences used in the production of a DNA construct, which is an expression cassette of the present invention, and an adeno-associated virus vector.
  • FIG. 5 is a graph showing an increase in promoter activity in cancer cells when the improved TSTA system of the present invention is used.
  • FIG. 6 is a diagram showing an increase in the expression of a target gene in cancer cells when the improved TSTA system of the present invention is used.
  • FIG. 6A shows the results of various cancer cells, and
  • FIG. 6B shows an enlarged graph of LNCaP cells.
  • FIG. 7 is a diagram showing a method for inserting a target-specific peptide into the outer shell of an adeno-associated virus.
  • FIG. 8 is a graph showing the efficiency of introduction of an adeno-associated virus vector having a target-specific peptide inserted into its outer shell into tumor cells.
  • 8A shows the results of HUVEC
  • FIG. 8B shows the results of SKOV-3
  • FIG. 8C shows the results of K562.
  • FIG. 9 is a diagram showing the results of primary lesion detection in orthotopic liver cancer model mice using the adeno-associated virus vector (AdTSTA / RGD-AAV-Luc) of the present invention.
  • FIG. 9A shows an outline of the examination schedule and an IVIS image
  • FIG. 9B shows a photograph of the tumor mass.
  • FIG. 9A shows an outline of the examination schedule and an IVIS image
  • FIG. 12 is a diagram showing a detection schedule of metastatic foci in a renal cancer hematogenous lung metastasis model mouse using the adeno-associated virus vector (AdTSTA / RGD-AAV-Luc) of the present invention.
  • FIG. 13 is a diagram showing the results of detection of metastasis in renal cancer hematogenous lung metastasis model mice using the adeno-associated virus vector (AdTSTA / RGD-AAV-Luc) of the present invention.
  • FIG. 13A shows the observation result (day 30) of the IVIS signal and macropathology in the control group
  • FIG. 13B shows the observation result (day 30) of the IVIS signal and macropathology in the group administered with AdTSTA / RGD-AAV-Luc.
  • FIG. 13A shows the observation result (day 30) of the IVIS signal and macropathology in the control group
  • FIG. 13B shows the observation result (day 30) of the IVIS signal and macropathology in the group administered with AdTSTA
  • FIG. 14 is a diagram showing a treatment schedule for metastatic foci in a renal cancer hematogenous lung metastasis model mouse using the adeno-associated virus vector (AdTSTA / RGD-AAV-REIC) of the present invention.
  • FIG. 15 is a diagram showing the therapeutic effect of metastases in renal cancer hematogenous lung metastasis model mice using the adeno-associated virus vector (AdTSTA / RGD-AAV-REIC) of the present invention.
  • FIG. 15A shows the IVIS signal and tissue Tunnel result (day 30) in the group administered with AdTSTA / RGD-AAV-AFP (control group), and
  • FIG. 15B shows the IVIS signal in the group administered with AdTSTA / RGD-AAV-REIC. The result of the tissue Tunnel (day 30) is shown.
  • FIG. 16 is a diagram showing an increase in expression of a target gene in various cancer cells when the improved TSTA system of the present invention is used.
  • the improved TSTA (advanced two-step transcription amplification) system of the present invention comprises a first expression cassette capable of expressing a transcription factor comprising a DNA construct in which a DNA sequence encoding a transcription factor is linked downstream of a specific promoter.
  • a second expression cassette comprising a DNA construct with a minimal promoter and target gene linked downstream of the GAL4 protein binding site is included.
  • the second expression cassette can express the target gene by the action of the transcription factor expressed by the first expression cassette.
  • the present invention is also a DNA construct comprising the first expression cassette and the second expression cassette described above.
  • the promoter located downstream of the GAL4 binding domain is an inducible promoter that is responsive to the transcription factor expressed by the first expression cassette, and uses a GAL4 responsive promoter, a TATA minimal promoter, and an adenovirus EIIb minimal promoter.
  • a GAL4 responsive promoter for example, the base sequence of DNA encoding the GAL4 binding site is shown in SEQ ID NO: 7, and the base sequence of the minimal promoter is shown in SEQ ID NO: 8.
  • the target gene is a target gene to be finally expressed by the improved TSTA system of the present invention, and a reporter gene that can be used for diagnosis of a disease such as cancer or a therapeutic gene that can be used for treatment of a disease such as cancer. Can be mentioned.
  • the promoter and the like are operably linked, and may further contain regulatory sequences such as an enhancer, terminator, and poly A sequence.
  • Reporter genes include luciferase (LUC) gene (SEQ ID NO: 10), fluorescent protein genes such as green fluorescent protein (GFP), fluorescent protein genes such as red fluorescent protein (DsRed), and ⁇ -glucuronidase (GUS) gene.
  • LOC luciferase
  • GFP green fluorescent protein
  • DsRed red fluorescent protein
  • GUS ⁇ -glucuronidase
  • the improved TSTA system acts, the transcription activity of a specific promoter is increased, and the target gene is expressed with high efficiency in the cell.
  • a reporter gene when used as a target gene, a specific target tissue or target cell can be detected by luminescence, PET (positron tomography) or the like.
  • a therapeutic gene when used as a target gene, the therapeutic gene is expressed in specific cells or tissues such as cancer cells related to the disease and exhibits a therapeutic effect.
  • the first expression cassette and the second expression cassette can be inserted into a vector, for example, and introduced into a cell via the vector.
  • the DNA construct containing the first expression cassette and the second expression cassette of the present invention can be used for experiments using cells in vitro, or introduced into non-human animals for animal experiments. It can also be used for disease detection and treatment.
  • the base sequence represented by SEQ ID NO: 14 the sequence consisting of the 1st to 3738th bases of the base sequence represented by SEQ ID NO: 14, ie, SEQ ID NO: 1 (corresponding to the 1st to 6th bases of SEQ ID NO: 14) ), SEQ ID NO: 2 (corresponding to the 7th to 461th bases of SEQ ID NO: 14), SEQ ID NO: 3 (corresponding to the 462th to 467th bases of SEQ ID NO: 14), SEQ ID NO: 4 (GAL4 DNA binding) DNA sequence encoding a domain; corresponding to nucleotides 468 to 911 of SEQ ID NO: 14, and SEQ ID NO: 5 (coding rat glucocorticoid receptor (Rat GR) inserted with DNA encoding polyglutamine (Poly Q
  • the present invention further includes a DNA encoding a GAL4 DNA binding domain (GAL4 DBD), a DNA encoding a glucocorticoid receptor (GR) inserted with a DNA encoding polyglutamine (Poly Q) or polyproline (PolyP).
  • GAL4 DBD GAL4 DNA binding domain
  • GR glucocorticoid receptor
  • a DNA encoding the transcriptional activation domain of VP16 which is a transcriptional regulator of HSV1 (herpes simplex virus), is a fusion DNA fused in this order, and includes a DNA construct encoding the transcriptional activation factor.
  • the DNA construct consists of the base sequence represented by SEQ ID NO: 22, for example.
  • the improved TSTA system of the present invention can increase the transcriptional activity of any specific promoter.
  • the present invention also includes a method for increasing the transcriptional activity of a specific promoter using the improved TSTA system. In this method, the first expression cassette and the second expression cassette described above are introduced into a cell in which a specific promoter is active.
  • the vector enables specific diagnosis or treatment of diseases such as cancer.
  • the vector can be prepared by inserting the first expression cassette and the second expression cassette into an adeno-associated virus.
  • a DNA construct in which the first expression cassette and the second expression cassette are linked may be inserted.
  • it may be inserted into two different adeno-associated virus vectors.
  • the two types of vectors may be introduced into the cells.
  • Adeno-associated virus is a parvovirus genus single-stranded DNA virus, and has the characteristics of (1) gene long-term expression, (2) low toxicity, and (3) gene transfer into dividing and non-dividing cells. The formation of concatamers (complexes in which single-stranded DNAs are linked) is the cause of long-term gene expression.
  • a DNA encoding a target cell-specific binding peptide that has directivity to a protein specifically expressed in a specific cell and binds to the cell is inserted into the outer shell (capsid) gene of the adeno-associated virus vector. And modify the outer shell.
  • the capsid-modified adeno-associated virus vector is directed to a specific cell that expresses a specific protein, reaches and binds to the cell, infects and is taken in, and an expression system within the cell Acts, the target gene is expressed in the cell, and can be used for diagnosis and treatment.
  • a peptide encoded by DAN that is inserted into the outer gene of an adeno-associated virus is a target-specific peptide that can bind to a protein that is selectively expressed in tumor cells or cells of a specific tissue or organ and is directed to the cells. is there.
  • Examples of such peptides include peptides having directivity for tumor vascular endothelial cells, and include peptides containing the amino acid sequence represented by the amino acid sequence RGD or NGR.
  • Peptides containing RGD include peptides that contain an RGD sequence and have binding affinity for cell surface integrins. For example, it is a peptide consisting of 5 to 20 amino acids including RGD.
  • the target-specific peptide can be freely changed via the linker. You can do it.
  • the adeno-associated virus vector can be produced by a known method.
  • US Pat. No. 5,858,351 describes a method for producing a recombinant adeno-associated virus that can be used in gene therapy (Kotin (1994) Human Gene Therapy 5: 793-801; Berns “Parvoviridae). and thereplication "Fundamental Virology, 2nd edition, edited by Fields & Knipe, etc.).
  • FIG. 2 shows a schematic diagram of an adeno-associated virus (AAV) vector capable of expressing a target gene by the improved TSTA system of the present invention and a structural diagram of an expression cassette which is a DNA construct introduced into the vector.
  • FIG. 2A shows a structural diagram of an expression cassette which is a DNA construct introduced into an adeno-associated virus vector containing hTERT as a specific promoter and a luciferase gene as a specific gene
  • FIG. 2B shows a specific gene containing hTERT as a specific promoter.
  • Is a diagram showing the structure of an expression cassette which is a DNA construct introduced into an adeno-associated virus vector containing the human REIC / Dkk-3 gene.
  • the nucleotide sequence represented by SEQ ID NO: 14 is SEQ ID NO: 1 (corresponding to the first to sixth bases of SEQ ID NO: 14), SEQ ID NO: 2 (hTERT core promoter sequence; corresponding to the seventh to 461th bases of SEQ ID NO: 14) ), SEQ ID NO: 3 (corresponding to nucleotides 462 to 467 of SEQ ID NO: 14), SEQ ID NO: 4 (DNA sequence encoding GAL4 DNA binding domain; corresponding to nucleotides 468 to 911 of SEQ ID NO: 14), SEQ ID NO: 5 (DNA sequence encoding rat glucocorticoid receptor (Rat GR) inserted with DNA encoding polyglutamine (Poly Q); corresponding to nucleotides 912 to 1163 of SEQ ID NO: 14), SEQ ID NO: 6 (VP16 DNA sequence encoding transcriptional activation domain; corresponding to bases 1164 to 1298 of SEQ ID NO: 14, SEQ ID NO: 7 (GAL4 DNA sequence
  • DNA encoding a protein or polypeptide consisting of can also be used for the construction of the DNA construct of the present invention.
  • stringent conditions are, for example, conditions of about “1XSSC, 0.1% SDS, 37 ° C.”, and more severe conditions are “0.5XSSC, 0.1% SDS, 42 ° C.” The condition is about “0.2XSSC, 0.1% SDS, 65 ° C.”. As the hybridization conditions become more severe in this way, it can be expected to isolate DNA having a high homology with the probe sequence.
  • combinations of the above SSC, SDS, and temperature conditions are exemplary, and necessary stringency can be realized by appropriately combining probe concentration, probe length, hybridization reaction time, and the like. .
  • the specific promoter sequence can be altered according to the cell to which it is directed, in which case the h-TERT core promoter sequence of SEQ ID NO: 14 or 20 is replaced with another promoter sequence. That's fine.
  • a reporter gene used for diagnosis and a gene used for treatment can be appropriately changed.
  • the gene of SEQ ID NO: 14 or 20 may be replaced with another gene.
  • the adeno-associated virus (AAV) vector capable of expressing a target gene by the improved TSTA system of the present invention can be used for disease detection or disease treatment.
  • Examples of the disease include cancer, and the like is directed to the cell by a peptide such as RGD that selectively binds to a protein expressed in a specific cell inserted in the outer shell of an adeno-associated virus vector.
  • the modified TSTA system acts in the cell and the target gene is expressed.
  • the target gene is a reporter gene such as a luciferase gene
  • specific cells can be detected by luminescence or the like.
  • a specific cell is a cancer cell, by administering to a subject, the cancer cell in a subject can be detected and it can be diagnosed that the subject is suffering from cancer. Since the adeno-associated virus vector of the present invention can detect one cell, it can be used, for example, for detection of a minute cancer.
  • lactose and magnesium stearate are used as carriers and excipients for tablets.
  • aqueous solution for injection isotonic solutions containing physiological saline, glucose and other adjuvants are used, and suitable solubilizers such as polyalcohols such as alcohol and propylene glycol, nonionic surfactants, etc. You may use together.
  • suitable solubilizers such as polyalcohols such as alcohol and propylene glycol, nonionic surfactants, etc. You may use together.
  • As the oily liquid, sesame oil, soybean oil and the like are used, and as a solubilizing agent, benzyl benzoate, benzyl alcohol and the like may be used in combination.
  • the present invention will be specifically described by the following examples, but the present invention is not limited to these examples.
  • FIG. 1 shows a conventional single step transcription system (FIG. 1A), a conventional two step translation system structure (FIG. 1B), and an improved two structure structure of the present invention. As shown in FIG.
  • a pGL3 basic vector containing a DNA construct for an improved TSTA system containing a hTERT promoter and a luciferase gene as a reporter gene is used for various cancer cells (PC3, Hep3B, HepG2, LNCaP, HeLa) and normal cells (OUMS, PrEC) were infected.
  • PC3, Hep3B, HepG2, LNCaP, HeLa normal cells
  • OUMS, PrEC normal cells
  • FIG. 5 shows the results of measuring the relative hTRET activity (hTERT activity in various cancer cells). The value when PC3 (prostate cancer) is 1.0 is shown by bar graph.
  • adenovirus-associated vector containing RGD in outer shell RGD (Arg-Gly-Asp) peptide 7 which is a ligand of ⁇ v integrin (expressed in many tumor blood vessels) is inserted into the AAV outer shell.
  • the tumor specific accumulation was examined.
  • a vector containing an improved TSTA system DNA construct containing the hTERT promoter was used.
  • GFP Green Fluorescent Protein
  • FIG. 8A, B, and C show the results for HUVEC, SKOV-3, and K562, respectively.
  • adeno-associated virus vector As the adeno-associated virus vector, an improved TSTA system DNA construct containing the hTERT promoter and RGD inserted into the outer shell was used. Moreover, luciferase was used as a reporter gene.
  • the adeno-associated virus vector is referred to as adAdTSTA / RGD-AAV-Luc.
  • adTSTA / RGD-AAV-Luc is incorporated into Hep3B (which is considered to be a small cancer) immediately after implantation, expresses a luciferase (Luc) gene, and then Hep3B cells expressing Luc proliferate and form a tumor mass It is thought that.
  • FIG. 9B shows a photograph of the tumor mass.
  • the model mouse used in this example is only an example of a primary microcancer, and the adeno-associated virus vector of the present invention has the property of being efficiently taken up by tumor tissue and expressing a gene only in tumor cells. Therefore, it is useful for diagnosis and monitoring of any primary microcancer.
  • FIG. 10 shows a treatment schedule.
  • FIG. 11B shows the result of the IVIS signal and tissue Tunnel (day 30) in the group administered with AdTSTA / RGD-AAV-REIC.
  • FIG. 11A shows the IVIS signal and tissue Tunnel results (day 30) in the group administered with AdTSTA / RGD-AAV-AFP (control group). As is apparent from the figure, the signal was almost lost at day 30 in the REIC treatment group, but the signal was clearly increased in the control group.
  • RENCA cell lung metastasis model mouse was used to examine the diagnosis and therapeutic effect in the hematogenous lung metastasis model.
  • the adeno-associated virus vector used was the same as that used in Example 4.
  • Fifty thousand RENCA cells were transplanted into the lung hemodynamically from the tail vein of Balbc nude mice (day 0).
  • 1010 particles of AdTSTA / RGD-AAV-Luc were administered from the tail vein (day 5).
  • PBS was administered. Thereafter, observation was performed periodically (day 8, day 20, day 30) by IVIS.
  • the experimental schedule is shown in FIG. FIG.
  • the model mouse used in this example is only an example of renal cancer hematogenous lung metastasis, and the adeno-associated virus vector of the present invention has the property of being efficiently incorporated into tumor tissue and expressing a gene only in tumor cells. Therefore, it is considered useful for monitoring any hematogenous metastatic cancer.
  • FIG. 15B shows the results of IVIS signal and tissue tunnel (day 30) in the group administered with AdTSTA / RGD-AAV-REIC.
  • FIG. 15A shows the result of IVIS signal and tissue tunnel (day 30) in the group administered with AdTSTA / RGD-AAV-AFP (control group).
  • the signal was almost lost at day 30 in the REIC treatment group, but the signal was clearly increased in the control group.
  • tissue Tunnel apoptosis detection
  • apoptosis was considered to be a major cause of therapeutic effect.
  • AdTSTA / RGD-AAV-REIC has therapeutic effects on renal cancer hematogenous lung metastases.

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Abstract

La présente invention concerne un système qui peut augmenter l'activité transcriptionnelle d'un promoteur spécifique pour augmenter l'expression spécifique d'un gène cible. La présente invention concerne spécifiquement un système pour augmenter l'activité transcriptionnelle d'un promoteur spécifique, qui comprend une première cassette d'expression et une deuxième cassette d'expression, où la première cassette d'expression comprend le promoteur spécifique et un ADN lié en aval du promoteur spécifique et préparé par fusion d'un ADN qui code pour un domaine de liaison d'ADN de GAL4, un ADN qui code pour un récepteur de glucocorticoïde (GR) ayant, inséré dans celui-ci, un ADN codant pour de la polyglutamine (Poly Q), et un ADN qui code pour un domaine d'activation de transcription pour VP16 dans cet ordre, la première cassette d'expression peut exprimer un facteur transcriptionnel qui est une protéine de fusion d'un domaine de liaison d'ADN de GAL4 (GAL4 DBD), un récepteur de glucocorticoïde (GR) ayant, inséré dans celui-ci, de la polyglutamine (Poly Q) ou de la polyproline (PolyP) et un domaine d'activation de transcription, et la seconde cassette d'expression est responsable du facteur transcriptionnel et comprend un promoteur inductible contenant un site de liaison de GAL4 (GAL4/TATA) et le gène cible lié en aval du promoteur inductible.
PCT/JP2010/056117 2009-03-30 2010-03-30 Système pour augmenter l'activité de promoteur spécifique, et vecteur portant le système WO2010114143A1 (fr)

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