WO2019045049A1 - Vecteur d'expression spécifique à une cellule de tubule rénal - Google Patents

Vecteur d'expression spécifique à une cellule de tubule rénal Download PDF

Info

Publication number
WO2019045049A1
WO2019045049A1 PCT/JP2018/032360 JP2018032360W WO2019045049A1 WO 2019045049 A1 WO2019045049 A1 WO 2019045049A1 JP 2018032360 W JP2018032360 W JP 2018032360W WO 2019045049 A1 WO2019045049 A1 WO 2019045049A1
Authority
WO
WIPO (PCT)
Prior art keywords
vector
gene
egfp
promoter
renal
Prior art date
Application number
PCT/JP2018/032360
Other languages
English (en)
Japanese (ja)
Inventor
内田　俊也
秀美代 渡邉
Original Assignee
学校法人帝京大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 学校法人帝京大学 filed Critical 学校法人帝京大学
Priority to JP2019539666A priority Critical patent/JPWO2019045049A1/ja
Publication of WO2019045049A1 publication Critical patent/WO2019045049A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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

Definitions

  • the present invention relates to renal tubular cell-specific expression vectors.
  • Priority is claimed on Japanese Patent Application No. 2017-168924, filed September 1, 2017, the content of which is incorporated herein by reference.
  • Renal tubules are tissues from the glomeruli in the kidney to the collecting ducts. In the process of raw urine passing through the renal tubule, it is reabsorbed and secreted. In renal tubules, there are sites called proximal tubule, Henreloop, thick Henle hook, distal tubule, collecting duct, etc. sequentially from the glomerulus side, and the shape and function are different for each site ing.
  • Barter's syndrome for example, is a disease characterized by dysfunction of the thick Henle's foot, which mainly affects children.
  • the symptoms of Barter syndrome include hypokalemia, metabolic alkalosis, blood pressure reduction and the like.
  • One of the causes of Barter syndrome is known to be an increase in function of a calcium-sensing receptor (CaSR) gene mutation.
  • CaSR calcium-sensing receptor
  • hereditary tubular diseases including Barter's syndrome
  • fundamental gene therapy has not been performed, but only symptomatic treatment has been performed.
  • the QOL of patients is extremely low, and the effects on complications due to complications on the kidney and the whole body are great, and an immediate solution is required.
  • Non-Patent Document 1 describes that a promoter of a sodium-potassium 2-chloride cotransporter (Nkcc2) gene, which is specifically expressed in the thick Henle's leg of the renal tubule, is cloned and analyzed.
  • Nkcc2 sodium-potassium 2-chloride cotransporter
  • An object of the present invention is to provide a vector for expressing a gene specifically in renal tubular cells.
  • a vector for expressing the gene specific to renal tubular cells which comprises a viral vector having a renal tubular cell specific promoter and a desired gene linked downstream of the promoter.
  • the promoter is sodium-dependent phosphate transporter type 2a (NPT2a), sodium-potassium-2-chloride cotransporter (NKCC2), aquaporin 2 (AQP2), sodium-chloride cotransporter (NCC), epithelial sodium-channel (ENaC)
  • NTT2a sodium-dependent phosphate transporter type 2a
  • NKCC2 sodium-potassium-2-chloride cotransporter
  • AQP2 aquaporin 2
  • NCC sodium-chloride cotransporter
  • ENaC epithelial sodium-channel
  • [3] The vector according to [1] or [2], wherein the gene is a gene selected from the group consisting of NPT2a, NKCC2, AQP2, NCC, and ENaC.
  • [4] The vector according to any one of [1] to [3], which is administered by bolus injection into a renal artery of a kidney whose blood flow has been blocked.
  • [5] The vector according to any one of [1] to [4], which is for gene therapy of hereditary tubular disease.
  • FIG. (A) and (b) is a photograph which shows the result of the immunohistochemical analysis of the kidney of the rat which introduce
  • FIG. (C) and (d) are photographs showing the results of immunohistochemical analysis of rat kidneys into which the NKCC2 pvu-EGFP adenoviral vector has been introduced in Experimental Example 4.
  • (E) and (f) are photographs showing the results of immunohistochemical analysis of rat kidneys into which the NKCC2-EGFP adenoviral vector has been introduced in Experimental Example 4.
  • FIG. (A) to (d) are photographs showing the results of immunostaining of the kidneys of rats into which the NKCC2DI-EGFP adenoviral vector has been introduced in Experimental Example 4 and observation with a confocal laser microscope.
  • (A) and (b) is a photograph which shows the result of the immunohistochemical analysis of the kidney of the rat which introduce
  • FIG. (A) to (d) are photographs showing the results of immunostaining of the kidney of a rat into which the NPT2a-EGFP adenoviral vector has been introduced in Experimental Example 5 and observation with a confocal laser microscope.
  • FIG. (A) is a photograph showing the result of detecting the nucleus
  • (b) is a photograph showing the result of detecting the EGFP
  • (c) is a photograph showing the result of detecting the endogenous NHE3 protein
  • (d) is a photograph in which (a) to (c) are synthesized.
  • (A) and (b) is a photograph which shows the result of the immunohistochemical analysis of the kidney of the rat which introduce
  • FIG. (A) to (d) are photographs showing the results of immunostaining of rat kidneys into which the AQP2-EGFP adenoviral vector has been introduced in Experimental Example 6 and observation with a confocal laser microscope.
  • (A) is a photograph showing the result of detecting the nucleus
  • (b) is a photograph showing the result of detecting the EGFP
  • (c) is a photograph showing the result of detecting the endogenous AQP2 protein
  • (d) is a photograph in which (a) to (c) are synthesized.
  • the present invention specifically expresses renal tubule cells specifically comprising a viral vector having a renal tubular cell specific promoter and a desired gene linked downstream of the promoter.
  • a viral vector having a renal tubular cell specific promoter and a desired gene linked downstream of the promoter.
  • the inventors succeeded in expressing a desired gene in renal tubular cells specifically in vivo by using the vector of the present embodiment. This is the first example of successful expression of a desired gene specifically in renal tubular cells.
  • the vector of this embodiment can be suitably used for the purpose of expressing a desired gene specifically in renal tubular cells in humans or animals.
  • renal tubular cell specific promoters include promoters of genes such as NPT2a, NKCC2, AQP2, NCC, and ENaC.
  • NPT2a is a gene also called SLC34A1, which is a gene specifically expressed in the proximal tubule.
  • NKCC2 is a gene also called SLC12A1, which is a gene specifically expressed in thick Henle's hook.
  • AQP2 is a gene specifically expressed in the collecting duct or distal tubule.
  • the renal tubular cell-specific promoter is preferably a promoter derived from a target species into which the vector of the present embodiment is to be introduced. However, it is also possible to express the desired gene using promoters from different species.
  • the nucleotide sequence of the renal tubular cell-specific promoter is preferably long. Moreover, it is preferable to include a base as close as possible to the translation initiation codon (ATG) or to include a translation initiation codon.
  • the length of a renal tubular cell specific promoter may be, for example, 2 kbp or more, for example, 3 kbp or more, for example, 4 kbp or more, for example, 5 kbp or more, for example, 6 kbp It may be more than.
  • the desired gene includes a gene transcriptionally controlled by the renal tubular cell-specific promoter described above. Specifically, genes such as NPT2a, NKCC2, AQP2, NCC, ENaC, etc. may be used.
  • the desired gene is preferably a gene from a species to which the vector of the present embodiment is to be introduced.
  • the desired gene is preferably a gene having no mutation causing disease. This makes it possible to use the vector of the present embodiment for gene therapy of hereditary tubular disease. That is, the vector of the present embodiment may be for gene therapy of hereditary tubular disease.
  • the desired gene is preferably a gene transcriptionally regulated by the native renal tubular cell-specific promoter.
  • the combination of renal tubular cell specific promoter and desired gene may be different from the original combination.
  • the virus vector is not particularly limited as long as it is generally used for gene transfer, and examples thereof include adenovirus vector, adeno-associated virus vector, lentivirus vector, retrovirus vector and the like.
  • the viral vector may be commercially available.
  • adenoviral vectors can be suitably used as viral vectors. It is preferable to use a viral vector which can not self-replicate from the viewpoint of viral propagation.
  • adenoviral vectors which can not replicate autonomously include those in which the E1A and E3 regions have been artificially deleted, adenochimeric viruses, modified adenovirus vectors and the like.
  • packaging cells having the corresponding deleted region.
  • packaging cells include HEK293 cells having E1A and E3 regions.
  • the vector of this embodiment is administered by bolus injection into the renal artery of the kidney which has blocked the blood flow.
  • Bolus injection is rapid injection.
  • the bolus injection is not particularly limited as long as the pressure is such that the kidney tissue of the patient is not injured.
  • injection may be performed in about 2 to 3 minutes per 1 ml of virus vector solution.
  • the blocking of the blood flow can be done by clamping the blood vessel with a clip. After blocking the renal artery, a bolus injection of viral vector is performed. In addition, after blocking the renal artery, it is preferable to infuse isotonic fluid such as physiological saline and wash out the blood in the kidney to increase infection efficiency more preferably. Furthermore, after injecting the viral vector, the infection efficiency of the viral vector can be further improved by blocking the renal vein and maintaining it for several minutes. Here, as a time for blocking the renal vein, for example, about 5 to 10 minutes can be mentioned.
  • the vector of the present embodiment may be formulated in the form of a pharmaceutical composition comprising the above-described viral vector and a pharmaceutically acceptable solvent.
  • a pharmaceutically acceptable solvent those used for the production of general pharmaceutical compositions can be appropriately used.
  • the present invention comprises administering to a patient in need of treatment an effective amount of a viral vector having a renal tubular cell specific promoter and a desired gene linked downstream of said promoter.
  • a method of treating hereditary tubular disease comprises administering to a patient in need of treatment an effective amount of a viral vector having a renal tubular cell specific promoter and a desired gene linked downstream of said promoter.
  • the present invention provides a vector for the treatment of hereditary tubular disease, which comprises a renal tubular cell-specific promoter and a desired gene linked downstream of said promoter. provide.
  • the present invention is the use of a vector for producing a therapeutic agent for hereditary tubular disease, wherein the vector is linked to a renal tubular cell specific promoter and downstream of the promoter.
  • the use is provided, which is a viral vector having the desired gene.
  • the above promoter may be a promoter of a gene selected from the group consisting of NPT2a, NKCC2, AQP2, NCC and ENaC.
  • the above gene may be a gene selected from the group consisting of NPT2a, NKCC2, AQP2, NCC and ENaC.
  • these genes are preferably genes having no mutation causing disease.
  • the above-mentioned vector is administered by bolus injection into the renal artery of the kidney which has blocked the blood flow.
  • accession number ENSMUSG00000027202 was used as the nucleotide sequence data of the 5 'side of the Npt2a gene.
  • base sequence data of accession number ENSRNOG00000015262 was used as base sequence data of the 5 'side of Nkcc2 gene.
  • base sequence data of accession number ENSRNOG00000000297 was used as base sequence data of the 5 'side of Aqp2 gene.
  • Npt2a gene Rat genomic DNA was extracted from the blood of Wistar rats, and the promoter of the Npt2a gene was cloned by PCR. In order to make the promoter region to be cloned as long as possible, a region including a region as close as possible to the translation initiation codon was obtained. The cloned promoter was in the region from -3379 to +630. Here, -1 corresponds to the base immediately before the translation initiation codon (ATG) of the Npt2a gene, and so forth.
  • Nkcc2 gene ⁇ Each promoter described in Table 1 below was used.
  • pNKCC2DI promoter and pNKCC2pvu promoter were distributed by Dr. Peter Igarashi, University of Texas Southwest Medical Center.
  • the pNKCC2 promoter was prepared by PCR of rat genomic DNA.
  • Promoter of Aqp2 gene >> Rat genomic DNA was extracted from the blood of Wistar rats, and the promoter of the Aqp2 gene was cloned by PCR. The cloned promoter was in the region of -5338 to +930.
  • Each prepared adenovirus vector was used by selecting a single clone correctly.
  • the nucleotide sequence of each adenoviral vector was confirmed by restriction enzyme cleavage and sequence analysis of the nucleotide sequence.
  • Each adenovirus vector was used to infect HEK 293 cells, a cell line derived from human embryonic kidney cells, to prepare adenovirus.
  • the titer of the obtained adenovirus was 10 13 pfu / mL or more.
  • the blood flow was interrupted by clamping with a clip between the rat's abdominal aorta and the left renal artery. Subsequently, 1 mL of saline was infused over 2 minutes into the left renal artery. Thereby, the blood in the kidney was washed away. Subsequently, 1 mL of adenoviral vector solution was infused into the left renal artery over 2 minutes. Subsequently, the renal vein was clamped with a clip to block blood flow and maintained for 10 minutes. As a result, the adenoviral vector remained in the kidney and efficiently infected the kidney cells. After that, the clip was removed and blood flow was resumed.
  • Rat renal artery was infused slowly with 1 mL of adenovirus vector solution for 16 hours.
  • adenoviral vector solution 1 mL of adenoviral vector solution.
  • adenoviral vectors were expected to backflow to the ureter and infect kidney cells.
  • Rat kidneys were directly injected with 1 mL of adenovirus vector solution. The injections were divided into 10 parts and injected in all directions.
  • kidneys were removed from each rat and fixed with 4% paraformaldehyde for 2 days. Subsequently, each kidney sample was embedded in paraffin to prepare a sliced section.
  • each tissue section was stained with anti-EGFP antibody, anti-NKCC2 antibody, anti-AQP2 antibody, anti-sodium-hydrogen exchanger 3 (NHE3; SLC9A3P2) antibody.
  • the anti-NHE3 antibody was used instead of the anti-NPT2a antibody because the anti-NPT2a antibody was not available.
  • the region where EGFP was expressed was limited to the site where the adenoviral vector was injected.
  • the structure of the renal parenchyma was damaged by repeated puncture and fluid injection.
  • adenoviral vectors were administered by bolus administration to the renal arteries.
  • Example 4 (examination of NKCC2 promoter)
  • the inventors administered the three types of adenoviral vectors, NKCC2DI-EGFP, NKCC2pvu-EGFP and NKCC2-EGFP, prepared in Experimental Example 2 to rats by bolus administration to the renal artery. Subsequently, 4 days after administration of the adenoviral vector, kidneys were removed from each rat, and tissue sections were prepared in the same manner as in Experimental Example 3.
  • FIGS. 1 (a) and (b) are photographs showing the results of introducing the NKCC2DI-EGFP adenoviral vector.
  • FIG. 1 (a) is a photograph showing the results of staining with anti-EGFP antibody
  • FIG. 1 (b) is a staining of another tissue section adjacent to the tissue section of FIG. 1 (a) with anti-NKCC2 antibody
  • Each scale bar shows 1 cm.
  • FIG.1 (c) and (d) are photographs which show the result of introduce
  • Fig. 1 (c) is a photograph showing the results of staining with anti-EGFP antibody
  • Fig. 1 (d) is another tissue section adjacent to the tissue section of Fig. 1 (c) stained with anti-NKCC2 antibody
  • Each scale bar shows 1 cm.
  • FIG. 1 (e) and (f) is a photograph which shows the result of introduce
  • FIG. 1 (e) is a photograph showing the results of staining with anti-EGFP antibody
  • FIG. 1 (f) is a staining of another tissue section adjacent to the tissue section of FIG. 1 (e) with anti-NKCC2 antibody, It is a photograph which shows the result of having detected sexual NKCC2 protein. Each scale bar shows 1 cm.
  • EGFP was expressed in a broader region than the endogenous NKCC2 protein.
  • FIGS. 2 (a) to 2 (d) are photographs showing the results of observation of the same field of view with a confocal laser microscope.
  • FIG. 2 (a) is a photograph showing the result of detecting the nucleus
  • FIG. 2 (b) is a photograph showing the result of detecting the EGFP
  • FIG. 2 (c) is a result of detecting the endogenous NKCC2 protein
  • FIG. 2 (d) is a photograph showing a composite of FIGS. 2 (a) to 2 (c). Scale bars all show 50 ⁇ m.
  • Non-Patent Document 1 it is reported that the pNKCC2 pvu promoter showed the highest promoter activity and the pNKCC2 DI promoter showed the lowest promoter activity in in vitro studies using primary culture cells of renal tubules.
  • the promoter is preferably as long as possible.
  • FIGS. 3 (a) and 3 (b) are photographs showing the results of introducing the NPT2a-EGFP adenoviral vector.
  • FIG. 3 (a) is a photograph showing the results of staining with anti-EGFP antibody
  • FIG. 3 (b) is a staining of another tissue section adjacent to the tissue section of FIG. 3 (a) with anti-NHE3 antibody
  • anti-NHE3 antibody was used instead of anti-NPT2a antibody because anti-NPT2a antibody was not available.
  • Each scale bar shows 1 cm.
  • FIGS. 4 (a) to 4 (d) are photographs showing the results of observation of the same field of view with a confocal laser microscope.
  • FIG. 4 (a) is a photograph showing the result of detecting the nucleus
  • FIG. 4 (b) is a photograph showing the result of detecting the EGFP
  • FIG. 4 (c) is a result of detecting the endogenous NHE3 protein
  • FIG. 4 (d) is a photograph showing a composite of FIGS. 4 (a) to 4 (c).
  • NPT2a-EGFP adenoviral vector makes it possible to express EGFP with an expression pattern close to that of the endogenous NKCC2 protein.
  • EGFP can be expressed in the same cells as cells expressing endogenous NHE3 protein.
  • FIGS. 5 (a) and (b) are photographs showing the results of introducing the AQP2-EGFP adenoviral vector.
  • Fig. 5 (a) is a photograph showing the results of staining with anti-EGFP antibody
  • Fig. 5 (b) is another tissue section adjacent to the tissue section of Fig. 3 (a) stained with anti-AQP2 antibody
  • Each scale bar shows 1 cm.
  • FIGS. 6 (a) to 6 (d) are photographs showing the results of observation of the same field of view with a confocal laser microscope.
  • FIG. 6 (a) is a photograph showing the result of detecting the nucleus
  • FIG. 6 (b) is a photograph showing the result of detecting the EGFP
  • FIG. 6 (c) is a result of detecting the endogenous AQP2 protein
  • FIG. 6 (d) is a photograph showing a composite of FIGS. 6 (a) to 6 (c). Scale bars all show 50 ⁇ m.
  • AQP2-EGFP adenoviral vector can express EGFP with an expression pattern close to that of endogenous AQP2 protein.
  • EGFP can be expressed in the same cells as cells expressing endogenous AQP2 protein.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Virology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Urology & Nephrology (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un vecteur destiné à provoquer l'expression d'un gène souhaité lié en aval d'un promoteur spécifique à une cellule de tubule rénal spécifiquement dans des cellules de tubule rénal, le vecteur comprenant un vecteur viral présentant le promoteur spécifique à une cellule de tubule rénal et le gène souhaité.
PCT/JP2018/032360 2017-09-01 2018-08-31 Vecteur d'expression spécifique à une cellule de tubule rénal WO2019045049A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2019539666A JPWO2019045049A1 (ja) 2017-09-01 2018-08-31 腎尿細管細胞特異的発現ベクター

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2017168924 2017-09-01
JP2017-168924 2017-09-01

Publications (1)

Publication Number Publication Date
WO2019045049A1 true WO2019045049A1 (fr) 2019-03-07

Family

ID=65527755

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2018/032360 WO2019045049A1 (fr) 2017-09-01 2018-08-31 Vecteur d'expression spécifique à une cellule de tubule rénal

Country Status (2)

Country Link
JP (1) JPWO2019045049A1 (fr)
WO (1) WO2019045049A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004111238A1 (fr) * 2003-06-16 2004-12-23 Tohoku Techno Arch Co., Ltd Sequence regulatrice de transcription
JP2008175630A (ja) * 2007-01-17 2008-07-31 Univ Of Miyazaki 急性腎不全の診断方法
JP2010506563A (ja) * 2006-10-12 2010-03-04 エシコン・インコーポレイテッド 組織修復および再生における腎臓由来細胞およびその使用方法
JP2014528076A (ja) * 2011-09-22 2014-10-23 ウニベルシダ デ ロス アンデス 早期における急性腎損傷をモニタリング、診断、および／または予後診断するための方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020184655A1 (en) * 1997-12-01 2002-12-05 Henryk Lubon Methods for the degradation and detoxification of organic material using urine produced by transgenic animals and related transgenic animals and proteins
JP2002525047A (ja) * 1998-09-16 2002-08-13 ネクシア バイオテクノロジーズ， インコーポレイテッド 尿における組換え蛋白質の産生
EP1135518A4 (fr) * 1998-11-13 2002-11-06 Univ New York Animaux transgeniques servant de bioreacteurs urinaires pour la production de proteines dans l'urine, constructions d'adn recombine pour l'expression specifique du rein, et procedes d'utilisation de ces dernieres
US9388427B2 (en) * 2002-12-02 2016-07-12 Biovec, Llc In vivo and ex vivo gene transfer into renal tissue using gutless adenovirus vectors
JP2010110322A (ja) * 2008-10-10 2010-05-20 Tohoku Univ ヒトｏａｔｐ−ｒ遺伝子導入モデル非ヒト動物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004111238A1 (fr) * 2003-06-16 2004-12-23 Tohoku Techno Arch Co., Ltd Sequence regulatrice de transcription
JP2010506563A (ja) * 2006-10-12 2010-03-04 エシコン・インコーポレイテッド 組織修復および再生における腎臓由来細胞およびその使用方法
JP2008175630A (ja) * 2007-01-17 2008-07-31 Univ Of Miyazaki 急性腎不全の診断方法
JP2014528076A (ja) * 2011-09-22 2014-10-23 ウニベルシダ デ ロス アンデス 早期における急性腎損傷をモニタリング、診断、および／または予後診断するための方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
IGARASHI P. ET AL.: "Cloning and Kidney Cell -specific Activity of the Promoter of the Murine Renal Na-K-Cl cotransporter Gene", J. BIOL. CHEM., vol. 271, no. 16, 1996, pages 9666 - 9674, ISSN: 0021-9258 *
OBERMULLER N. ET AL.: "Expression of the Na-K-2Cl Cotransporter by Macula Densa and Thick Ascending Limb Cells of Rat and Rabbit Nephron", J. CLIN. INVEST., vol. 98, no. 3, 1996, pages 635 - 640, XP055578946, ISSN: 0021-9738 *
WATANABE S. ET AL.: "Targeting gene expression to specific cells of kidney tubules in vivo, using adenoviral promoter fragments", PLOS ONE, vol. 12, no. 3, 2 March 2017 (2017-03-02), pages 1 - 14, XP055578926, ISSN: 1932-6203 *
WEINMAN E.J. ET AL.: "The role of NHERF-1 in the regulation of renal proximal tubule sodium-hydrogen exchanger 3 and sodium-dependent phosphate cotransporter 2a", J. PHYSIOL., vol. 567, no. 1, 2005, pages 27 - 32, XP055578944, ISSN: 1469-7793 *

Also Published As

Publication number Publication date
JPWO2019045049A1 (ja) 2020-12-03

Similar Documents

Publication Publication Date Title
ES2429034T3 (es) Uso de antagonistas de ANGPTL3 para el tratamiento de enfermedades hepáticas
White et al. Myocardial gene delivery using molecular cardiac surgery with recombinant adeno-associated virus vectors in vivo
US20150139952A1 (en) Methods, compositions, cells, and kits for treating ischemic injury
JP2011148834A (ja) インターフェロン耐性腫瘍の処置のための方法および組成物
JP6726291B2 (ja) 心筋線維化の処置のための医薬組成物
US20230049180A1 (en) Hydrodynamic Methods for Delivering Fluids to Kidney Tissues and Related Materials and Methods
KR20040104685A (ko) 내피 세포 특이성을 보이는 프로모터 및 이의 이용 방법
JP6014029B2 (ja) Ｒｅｉｃ発現アデノウイルスベクター
WO2024140765A1 (fr) Arn et médicament contenant de l'arn
JP2023530171A (ja) 筋肉内及び心臓内でのｓｇｃｇの適切な発現を可能にする遺伝子療法発現系
EP1443970A2 (fr) Promoteurs presentant une specificite pour des cellules endotheliales et leurs procedes d'utilisation
WO2019045049A1 (fr) Vecteur d'expression spécifique à une cellule de tubule rénal
Saleh et al. Duchenne muscular dystrophy disease severity impacts skeletal muscle progenitor cells systemic delivery
US20200270638A1 (en) Exosomes as a vector for gene delivery in resistance to neutralizing antibody and methods of their manufacture
CN116019935A (zh) Ago2在制备治疗心衰或糖尿病性心肌病的药物方面的用途及其蛋白、基因、转化体
KR20190050277A (ko) 허혈성 심혈관 질환의 치료용 또는 예방용 약학 조성물
JP7193849B2 (ja) 虚血組織に集積するエクソソームおよびその製造方法
KR20090035711A (ko) 유전자 치료를 위한 아데노-관련 바이러스 벡터의 전방 심외막 관상에의 연장 주입
WO2007083603A1 (fr) Agent thérapeutique
CN114504658B (zh) 一种治疗阿霉素诱导的心脏毒性损伤的药物及应用
Kilian et al. Adeno-associated virus-mediated gene transfer in a rabbit vein graft model
JP4843767B2 (ja) がん細胞特異的遺伝子発現法を用いた血管新生阻害薬
RU2628706C2 (ru) Способ стимуляции ангиогенеза в ишеминизированных тканях и комбинированное лекарственное средство для осуществления способа
CN118286434A (zh) Ythdf3抑制剂在制备防治病理性心肌肥厚和心室重构的药物中的应用
Tomasoni et al. AAV9-mediated engineering of autotransplanted kidney of non-human primates

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18850965

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019539666

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18850965

Country of ref document: EP

Kind code of ref document: A1