WO2011162115A1 - 膵臓β細胞増殖因子を利用した医薬組成物 - Google Patents
膵臓β細胞増殖因子を利用した医薬組成物 Download PDFInfo
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- WO2011162115A1 WO2011162115A1 PCT/JP2011/063459 JP2011063459W WO2011162115A1 WO 2011162115 A1 WO2011162115 A1 WO 2011162115A1 JP 2011063459 W JP2011063459 W JP 2011063459W WO 2011162115 A1 WO2011162115 A1 WO 2011162115A1
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- G01N2333/90—Enzymes; Proenzymes
- G01N2333/91—Transferases (2.)
- G01N2333/91091—Glycosyltransferases (2.4)
- G01N2333/91097—Hexosyltransferases (general) (2.4.1)
- G01N2333/91102—Hexosyltransferases (general) (2.4.1) with definite EC number (2.4.1.-)
Definitions
- the present invention relates to a pharmaceutical composition using a UDP-glucose glycoprotein glucosetransferase 1 (UDP-glucose-glycoprotein-glycosyl-transferase-1, hereinafter referred to as "UGGT1") or a gene encoding the same, a screening method, and the like.
- UDP-glucose glycoprotein glucosetransferase 1 UDP-glucose-glycoprotein-glycosyl-transferase-1
- UGGT1 UDP-glucose glycoprotein glucosetransferase-1
- Diabetes is a modern national disease (expected to be around 14.7 million including the reserve army), and many Japanese people develop from insulin secretion failure.
- the number of pancreatic islets of the pancreas that secrete insulin is small, especially in diabetic patients, and regenerative medicine of ⁇ cells is extremely important.
- Non-patent Document 6 There are several types of regenerative factors known to date that increase pancreatic ⁇ cells. For example, Pdx1 (Non-patent document 1, Non-patent document 2), Mafa (Non-patent document 3), Ngn3 (Non-patent document 3), GLP-1 (Non-patent document 4), Liver erk (Non-patent document 5) , Osteocalcin (Non-patent Document 6) and the like.
- pancreatic ⁇ -cell growth factor described above only increases the pancreatic ⁇ -cells by about 2 to 3 times compared to the wild type.
- a factor having a higher proliferative effect is desired.
- the present invention has been made based on such a technical background, and an object thereof is to provide a pancreatic ⁇ -cell growth factor having a high proliferative action.
- the present inventor has shown that the protein UGGT1 has a proliferating action on pancreatic ⁇ cells and that the proliferating action is significantly higher than known pancreatic ⁇ cell growth factors. I found.
- UGGT1 and its gene are known, it was not known that this protein has a proliferative action on pancreatic ⁇ cells. Although a mouse in which the UGGT1 gene was knocked out has been produced (Cited document 1), the pancreas was not analyzed because it was lethal during the fetal period.
- the present invention has been completed based on the above findings.
- the present invention provides the following (1) to (8).
- a pharmaceutical composition comprising a vector expressing the UGGT1 gene.
- the pharmaceutical composition according to (1) which is used for prevention or treatment of diabetes.
- a step of culturing the cell according to (5) or (6) in the presence of a test substance and a step of selecting a test substance having an increased expression level of a reporter gene.
- a screening method for prophylactic or therapeutic agents A step of coexisting a test substance with UGGT1, selecting a test substance that interacts with UGGT1, and administering the test substance selected above to a non-human animal to proliferate pancreatic ⁇ cells of the non-human animal
- UGGT1 contained in the pharmaceutical composition of the present invention has a strong proliferation action on pancreatic ⁇ cells. Therefore, the pharmaceutical composition of the present invention is useful as a preventive or therapeutic agent for diabetes. UGGT1 is also useful as a target substance for the development of diabetes therapeutics.
- the arrows indicate the islets of Langerhans.
- the scale bar in the lower left is 1000 ⁇ m.
- 1 WT represents a wild-type mouse
- 2 P represents a mouse into which the Pdx1 gene was introduced (cited references 2 and 3)
- 3PNM represents a mouse into which the Pdx1 gene, the Ngn3 gene, and the Mafa gene were introduced
- 4 G indicates a mouse in which the GLP1 gene is introduced (reference document 5)
- 5E indicates a mouse in which the erk gene is introduced into the liver (reference document 6)
- 6 O indicates that an osteocalcin gene is introduced.
- Streptozotocin was collected in wild type (WT) and UGGT1 (TG) mice immediately before administration (D0) and 48 hours later (D2), and the insulin concentration was measured. In the wild-type mice, the insulin concentration was significantly (***; p ⁇ 0.0001) decreased by the administration of streptozotocin, while in the UGGT1 mice, no significant decrease was observed (#; p> 0.05).
- the pharmaceutical composition of the present invention is characterized by containing a vector expressing the UGGT1 gene.
- UGGT1 is a known protein, and the base sequence of the gene encoding it (UGGT1 gene) is also published on databases such as NCBI and GenBank.
- UGGT1 gene the base sequence of the gene encoding it
- the UGGT1 protein and UGGT1 gene used may be natural, but consists of an amino acid sequence in which one or several amino acids are deleted, substituted or added in the amino acid sequence of natural UGGT1, and is the same as natural UGGT1
- a modified UGGT1 having a ⁇ -cell proliferation action and a gene encoding the same may be used.
- UGGT1 gene is inserted into a vector together with an appropriate promoter.
- the promoter the promoter of the UGGT1 gene itself may be used, and other promoters may be used.
- a promoter other than the promoter of the UGGT1 gene a promoter capable of expressing the UGGT1 gene in the pancreas is preferable, and examples thereof include an insulin II promoter and an insulin I promoter.
- Vectors that can be used for gene therapy can be used.
- viral vectors include adenovirus vectors, retrovirus vectors, AAV vectors, SV40 vectors, and the like.
- the administration method of the pharmaceutical composition of the present invention is not particularly limited, and can follow the method used in general gene therapy.
- it can be administered by intradermal, intraperitoneal, intravenous, arterial, spinal fluid injection or infusion.
- the dosage of the pharmaceutical composition of the present invention is not particularly limited, and can be appropriately selected according to the administration form, administration route, properties of the administration subject, and the like.
- a general dose is 10 mg to 1000 mg as the weight of UGGT1 gene per day for adults.
- the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is administered by injection or infusion, it may contain components usually contained in injection solutions or infusion solutions.
- Such components include liquid carriers (for example, potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, polyethylene glycol, vegetable oils, ethanol, glycerin, dimethyl sulfoxide, propylene glycol, etc.), antibacterial agents And local anesthetics (eg, procaine hydrochloride, dibucaine hydrochloride, etc.), buffer solutions (eg, Tris-HCl buffer solution, Hepes buffer solution, etc.), osmotic pressure regulators (eg, glucose, sorbitol, sodium chloride, etc.) .
- liquid carriers for example, potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, polyethylene glycol, vegetable oils, ethanol, glycerin, dimethyl sulfoxide, propylene glycol, etc.
- the pharmaceutical composition of the present invention can be used for the prevention and treatment of diabetes.
- the pharmaceutical composition of the present invention is effective for both type 1 diabetes and type 2 diabetes, but is expected to be particularly effective for type 1 diabetes because it can regenerate ⁇ cells.
- the pharmaceutical composition of the present invention is used for humans, but may be administered to animals other than humans to proliferate pancreatic ⁇ cells of the animals.
- target animals include mice, rats, dogs, monkeys, and the like.
- UGGT1 gene can be used not only for pharmaceutical composition but also for production of transgenic animals.
- a transgenic animal expressing the UGGT1 gene can be produced by injecting a vector expressing the UGGT1 gene into a fertilized egg of a non-human animal and transplanting the fertilized egg into a foster parent animal.
- animals to be produced include mice, rats, dogs, monkeys and the like.
- UGGT1 proliferates pancreatic ⁇ -cells
- substances that increase the amount of UGGT1 in the body (substance A) and substances that enhance the pancreatic ⁇ -cell proliferating action of UGGT1 (substance B) can be candidates for diabetes treatment. . Therefore, a new preventive or therapeutic agent for diabetes can be found by screening the substance A or substance B.
- a step of culturing cells transformed with a vector in which a reporter gene is linked downstream of a promoter of UGGT1 gene in the presence of a test substance, and the expression level of the reporter gene were increased.
- a method including the step of selecting a test substance can be exemplified.
- the substance that increases the expression level of the reporter gene in the cells is expected to increase the activity of the promoter of the UGGT1 gene in vivo and increase the expression level of the UGGT1 gene in vivo. Therefore, the substance obtained by this screening method can be a prophylactic or therapeutic agent for diabetes.
- the reporter gene to be used may be one generally used for screening methods and the like, and for example, GFP gene, luciferase gene, alkaline phosphatase gene, ⁇ gal gene and the like can be used.
- the promoter sequence of UGGT1 gene is known and published on the database.
- the promoter of the mouse-derived UGGT1 gene is present on mouse chromosome 1, its nucleotide sequence is registered as accession numbers NT_039170, NM_001030649, etc., and the human-derived UGGT1 gene is present on human chromosome 2.
- the base sequences are registered as accession numbers NT_022135, NW_921507, NW_001838849, etc.
- the rat-derived UGGT1 gene is present on the rat chromosome 9, and the base sequences are registered as accession numbers NW_047814, NW_001084882, etc. Yes.
- Preparation of a vector in which a reporter gene is linked downstream of the promoter of the UGGT1 gene and cell transformation thereby can be performed according to conventional methods.
- the cells used are preferably pancreatic ⁇ cells.
- pancreatic ⁇ cells for example, NIT-1 cells, MIN6 cells, RIN5 cells and the like can be used.
- Whether or not the test substance has increased the expression level of the reporter gene can be determined by comparing the expression level of the reporter gene in cells cultured in the absence of the test substance.
- a test substance is allowed to coexist with UGGT1, a test substance that interacts with UGGT1 is selected, and the test substance selected above is administered to a non-human animal.
- a method including the step of selecting a test substance for proliferating pancreatic ⁇ -cells can be exemplified.
- the test substance can be narrowed down by selecting such a substance.
- the substances selected here include substances that interact with UGGT1 but do not affect the ⁇ -cell proliferation action and substances that inhibit UGGT1 beta-cell proliferation action. Yes. Therefore, by administering the selected substance to a non-human animal and examining the proliferation state of pancreatic ⁇ cells of the non-human animal, it is possible to select only substances that eliminate the aforementioned substances and enhance the ⁇ -cell proliferation action .
- Whether or not to interact with UGGT1 can be determined according to methods generally applied to screening methods and the like. Examples of such methods include two-hybrid, one-hybrid, FRET, HTRF, and LANCE.
- the same animals as the transgenic animals described above can be used.
- Example 1 Preparation of UGGT1 mouse An expression vector in which the UGGT1 gene was incorporated into a rat insulin II promoter gene (sequences 243 to 1125 described in RATINSII registered in GeneBank) was constructed, and C3H and C57Black6 mice were used. The fertilized egg was injected, and the fertilized egg was placed in a temporary parent mouse. After birth of F0 mice, the genotype was confirmed with PCR primers 199M (5'-GCTCTGACTGACCGCGTTACTCC-3 ': SEQ ID NO: 1) and 201M (5'-GGGAGTGTCCCAGGAATCAGG-3': SEQ ID NO: 2), and mated 6 times to C57Black6 mice. I let you. The expression of the UGGT1 gene in the F6 mouse (6 months old) was analyzed by RT-PCR. As a result, the introduced UGGT1 gene was specifically expressed in the pancreas at the RNA level (FIG. 1).
- FIG. 3 shows the number of pancreatic islets of Langerhans in UGGT1 mice and mice expressing a known pancreatic ⁇ -cell growth factor.
- the number of cells is calculated based on the data existing in the texts and figures in the papers that contain known factors (cited references 2-7), and the relative value when the wild type of each paper is set to 1. Expressed in As shown in the figure, the number of cells in the pancreatic islets of Langerhans was at most several times that of the wild type in mice expressing a known factor, but about 100 times in UGGT1 mice.
- Example 2 Analysis of therapeutic effect of UGGT1 in diabetes model animal As shown in Figs. 2 and 3, the number of cells of pancreatic islets of Langerhans was significantly increased in UGGT1 mice. Therefore, streptozotocin was administered to UGGT1 mice to induce diabetes, and an analysis of the therapeutic effect of UGGT1 was attempted. Streptozotocin is a reagent that specifically kills pancreatic ⁇ -cells and lowers insulin levels to induce diabetes. Blood was collected before administration (D0), and further blood was collected 48 hours after administration (D2), and the blood glucose level and insulin concentration were assayed.
- the blood glucose level was 200 mg / dL or less for both wild type and UGGT1 mice before administration, and no significant difference was observed.
- the wild-type blood glucose level after administration was about 400 mg / dL, significantly (p ⁇ 0.0001) higher than before administration, and induced diabetes.
- the blood glucose level of UGGT1 mice was about 250 mg / dL, which was not significantly different from that before administration and did not induce diabetes (FIG. 4).
- Citation 4 Qiao Zhou, Juliana Brown, Andrew Kanarek, Jayaraj Rajagopal, Douglas A Melton. In vivo reprogramming of adult pancreatic exocrine cells to b-cells. Nature 455: 627-633, 2008. Reference 5: Doris A Stoffers, Timothty J Kieffer, Mehboob A Hussain, Daniel J Drucker, Susan Bonner-Weir, Joel F Habener, Josephine M Egan. Insulinotropic Glucagon-like peptide 1 stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 49: 741-748, 2000.
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Abstract
Description
(1)UGGT1遺伝子を発現するベクターを含有することを特徴とする医薬組成物。
(2)糖尿病の予防又は治療に用いられることを特徴とする(1)に記載の医薬組成物。
(3)(1)又は(2)に記載の医薬組成物を非ヒト動物に投与し、その非ヒト動物の膵臓β細胞を増殖させる方法。
(4)UGGT1遺伝子が導入され、この遺伝子が発現していることを特徴とするトランスジェニック非ヒト動物。
(5)UGGT1遺伝子のプロモーターの下流にレポーター遺伝子を連結したベクターで形質転換された細胞。
(6)細胞が、膵臓β細胞であることを特徴とする(5)に記載の細胞。
(7)被験物質の存在下で(5)又は(6)に記載の細胞を培養する工程、及びレポーター遺伝子の発現量を増大させた被験物質を選択する工程を含むことを特徴とする糖尿病の予防薬又は治療薬のスクリーニング方法。
(8)被験物質をUGGT1と共存させ、UGGT1と相互作用をする被験物質を選択する工程、及び前記で選択された被験物質を非ヒト動物に投与し、その非ヒト動物の膵臓β細胞を増殖させる被験物質を選択する工程を含むことを特徴とする糖尿病の予防薬又は治療薬のスクリーニング方法。
ラットインスリンIIプロモーター遺伝子(GeneBankに登録されているRATINSIIに記してある配列の243から1125)にUGGT1遺伝子を組み込んだ発現ベクターを構築し、C3Hマウス及びC57Black6マウスの受精卵に注入し、仮親マウスに同受精卵を入れた。F0マウス出生後、遺伝子型をPCRプライマー199M(5’-GCTCTGACTGACCGCGTTACTCC-3’: 配列番号1)及び201M(5’-GGGAGTGTCCCAGGAATCAGG-3’: 配列番号2)にて確認し、C57Black6マウスへ6回交配させた。そのF6マウス(6ヶ月齢)のUGGT1遺伝子の発現をRT-PCRにより解析した。その結果、導入したUGGT1遺伝子はRNAレベルで膵臓に特異的に発現していた(図1)。
図2及び図3に示すように、UGGT1マウスでは、膵臓ランゲルハンス島の細胞数が顕著に増加していた。そこで、UGGT1マウスにストレプトゾトシンを投与し、糖尿病を誘発させて、UGGT1の治療効果の解析を試みた。ストレプトゾトシンは、膵臓β細胞を特異的に殺し、インスリン濃度を下げて、糖尿病を誘発させる試薬である。投与前に採血し(D0)、投与後48時間後さらに採血し(D2)、その血糖値、インスリン濃度の検定を行った。
引用文献1:Maurizio Molinari, Camela Galli, Omar Vanoni, Stacey M Arnold, Randal J Kaufman.
Persistent glycoprotein misfolding activities the glucosidase II/UGT1-driveb Calnexin cycle to delay aggregation and loss of folding competence.
Molecular Cell vol20, p503-512, 2005
引用文献2:Rui Takahashi, Hisanitsu Ishuhara, KazumaTakahashi, Akira Tamura, Suguru Yamaguchi, Takahiro Yamada, Hideki Katagiri, Yoshitomo Oka.
Efficient and controlled gene expression in mouse pancreatic isltes by arterial delivery of tetracycline-inducible adenoviral vectors.
Journal of Molecular Endocrinology 38:127-136, 2007.
引用文献3:Junta Imai, Hideki Katagiri, Tatsuya Yamada, Yasushi Ishigaki, Takehide Ogihara, Kenji Uno, Yutaka Hasegawa, Junhong Gao, Hisamitsu Ishihara, Hironobu Sasano, Hiroyuki Mizuguchi, Tomoichiro Asano, Yoshitomo Oka.
Constitutively active PDX1 induced efficient insulin production in adult murine liver.
Biochemical and Biophysical Research Communications 326:4022-409, 2005.
引用文献4:Qiao Zhou, Juliana Brown, Andrew Kanarek, Jayaraj Rajagopal, Douglas A Melton.
In vivo reprogramming of adult pancreatic exocrine cells to b-cells.
Nature 455:627-633, 2008.
引用文献5:Doris A Stoffers, Timothty J Kieffer, Mehboob A Hussain, Daniel J Drucker, Susan Bonner-Weir, Joel F Habener, Josephine M Egan.
Insulinotropic Glucagon-like peptide 1 stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas.
Diabetes 49:741-748, 2000.
引用文献6:Junta Imai, Hideki Katagiri, Tetsuya Yamada, Yasushi Ishigaki, Toshinobu Suzuki, Hirohito Kudo, Kenji Uno, Yutaka Hasegawa, Junhong Gao, Keizo Kaneko, Hisamitsu Ishihara, Akira Niijima, Masamitsu Nakazato, Tomoichiro Asano, Yasuhiro Minokoshi, Yoshitomo Oka.
Reluration of pancreatic b cell mass by neuronal signals from the liver.
Science 322:1250-1254, 2008.
引用文献7:Na Kyung Lee, Hideaki Sowa, Eiichi Hinoi, Mathieu Ferron, Jong Deok Ahn,
Cyrille Confavreux, Romain Dacquin, Patrick J Mee, Marc D McKee, Dae Young Jung, Zhiyou Zhang, Jason K Kim, Franck Mauvais-Jarvis, Patricia Ducy, Gerard Karsenty.
Endocrine regulation of energy metabolism by the skeleton.
Cell 130:456-469, 2007.
Claims (8)
- UGGT1遺伝子を発現するベクターを含有することを特徴とする医薬組成物。
- 糖尿病の予防又は治療に用いられることを特徴とする請求項1に記載の医薬組成物。
- 請求項1又は2に記載の医薬組成物を非ヒト動物に投与し、その非ヒト動物の膵臓β細胞を増殖させる方法。
- UGGT1遺伝子が導入され、この遺伝子が発現していることを特徴とするトランスジェニック非ヒト動物。
- UGGT1遺伝子のプロモーターの下流にレポーター遺伝子を連結したベクターで形質転換された細胞。
- 細胞が、膵臓β細胞であることを特徴とする請求項5に記載の細胞。
- 被験物質の存在下で請求項5又は6に記載の細胞を培養する工程、及びレポーター遺伝子の発現量を増大させた被験物質を選択する工程を含むことを特徴とする糖尿病の予防薬又は治療薬のスクリーニング方法。
- 被験物質をUGGT1と共存させ、UGGT1と相互作用をする被験物質を選択する工程、及び前記で選択された被験物質を非ヒト動物に投与し、その非ヒト動物の膵臓β細胞を増殖させる被験物質を選択する工程を含むことを特徴とする糖尿病の予防薬又は治療薬のスクリーニング方法。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2019173005A (ja) * | 2018-03-29 | 2019-10-10 | 三菱ケミカル株式会社 | 粘着シート、積層シート及びそれを用いた画像表示装置 |
JP7322454B2 (ja) | 2018-03-29 | 2023-08-08 | 三菱ケミカル株式会社 | 粘着シート、積層シート及びそれを用いた画像表示装置 |
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EP2583693A1 (en) | 2013-04-24 |
JPWO2011162115A1 (ja) | 2013-08-19 |
EP2583693A4 (en) | 2013-12-25 |
US20130086704A1 (en) | 2013-04-04 |
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