DK2768948T3 - Fremstilling af en human beta-cellelinje fra en tidlig postnatal bugspytkirtel - Google Patents
Fremstilling af en human beta-cellelinje fra en tidlig postnatal bugspytkirtel Download PDFInfo
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- DK2768948T3 DK2768948T3 DK12781298.0T DK12781298T DK2768948T3 DK 2768948 T3 DK2768948 T3 DK 2768948T3 DK 12781298 T DK12781298 T DK 12781298T DK 2768948 T3 DK2768948 T3 DK 2768948T3
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Claims (14)
1. Fremgangsmåde til fremstilling af humane pankreatiske beta-celler eller humane beta-celle tumorer, omfattende trinnene: a) at dissociere neonatalt humant pankreasvæv fra et individ på mindre end 5 år med collagenase in vitro for at opnå neonatale humane pankreasceller, b) at transducere og co-transducere de neonatale humane pankreasceller opnået i trin a) med i) en lentivirusvektor der udtrykker stort T-antigen af SV40 under kontrollen af insulinpromoteren eller ii) med en lentivirusvektor der udtrykker stort T-antigen af SV40 under kontrollen af insulinpromoteren og en lentivirusvektor der udtrykker hTERT under kontrollen af insulinpromoteren, eller iii) en lentivirusvektor der udtrykker både stort T-antigen af SV40 og hTERT, c) at indføre de transducerede neonatale pankreasceller opnået i b) i nyrekapslen af et ikke-menneskeligt dyr med svær kombineret immundefekt (scid), d) at tillade de transducerede pankreasceller at udvikle insulinom-lignende strukturer, hvor de neonatale humane pankreasceller i insulinom-lignende strukturer er differentierede i insulinproducerende pankreatiske beta-celler; e) at mikrodissekere de insulinom-lignende strukturer opnået i trin d), for derved at dissociere cellerne deraf, f) at sub-transplantere cellerne opnået i trin e) ind i nyrekapslen af et nyt ikke-menneskeligt dyr med scid, g) at tillade de sub-transplanterede celler i trin f) at udvikle og regenerere insulinom-lignende strukturer, hvor de nyudviklede insulinom-lignende strukturer er beriget i insulinproducerende pankreatiske beta-celler; h) at mikrodissekere de insulinom-lignende strukturer opnået i trin g), og at dissociere og indsamle cellerne deraf, i) eventuelt, at sub-transplantere cellerne opnået i trin g) ind i nyrekapslen af et nyt ikke-menneskeligt dyr med scid, for derved at tillade yderligere berigelse og amplifikation af insulinproducerende pankreatiske beta-celler; og j) eventuelt at gentage trinnene f), g) og h), indtil den passende mængde af insulinproducerende pankreatiske beta-celler opnås.
2. Fremgangsmåden ifølge krav 1, hvor konstruktionen af lentivirusvektorerne tillader reversibel eller betinget immortalisering.
3. Fremgangsmåden ifølge et hvilket som helst af kravene 1 eller 2, hvor lentivirusvektorerne omfatter mindst et LoxP-sted og stort T-antigenet af SV40 og/eller hTERT-genet fjernes ved virkningen af Cre-rekombinasen.
4. Fremgangsmåden ifølge et hvilket som helst af kravene 1 eller 2, hvor lentivirusvektorerne omfatter mindst et FRT-sted og stort T-antigenet af SV40 og/eller hTERT-genet fjernes ved virkningen af FLP-rekombinasen.
5. Fremgangsmåden ifølge et hvilket som helst af kravene 1 eller 2, hvor lentivirusvektoren der udtrykker stort T-antigen af SV40 og lentivirusvektoren der udtrykker hTERT yderligere omfatter et LoxP- eller et FLP-sted, forudsat at de sted-specifikke rekombinationssteder er forskellige i vektorerne.
6. Fremgangsmåden ifølge et hvilket som helst af kravene 3 til 5, hvor et negativt selektionstrin udføres efter virkningen af Cre- eller FLP-rekombinasen for kun at selektere cellerne, hvor de immortaliserede gener stort T-antigen af SV40 og/eller hTERT er blevet fjernet.
7. Fremgangsmåden ifølge et hvilket som helst af kravene 3 til 5, hvor lentivirusvektorerne inkluderer mindst et negativt selektions-markørgen.
8. Fremgangsmåden ifølge krav 7, hvor det negative selektions-markørgen vælges fra gruppen udgjort af HSV-TK-genet, hypoxanthin-phosphoribosyl-transferase (HPRT)-genet, guanin-phosphoribosyl-transferase (Gpt)-genet, og cytosin-deaminase-genet.
9. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 8, hvor det ikke-menneskelige dyr med scid er en scid-mus.
10. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 9, yderligere omfattende at transducere cellerne af trin e) med en lentivirusvektor der udtrykker et antibiotisk resistensgen under kontrollen af insulinpromoteren.
11. Fremgangsmåden ifølge krav 10, hvor det antibiotiske resistensgen er et neomycin-resistensgen.
12. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 11, yderligere omfattende at indsamle de humane pankreatiske beta-celler opnået at trin j) for at danne en homogen cellepopulation og eventuelt at dyrke populationen in vitro for at etablere en human funktionel beta-cellelinje.
13. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 12, hvor collagenasen er collagenase XI.
14. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 13, yderligere omfattende et eller flere de-immortaliseringstrin, der inkluderer at fjerne stort T-antigenet af SV40, hTERT og/eller de antibiotiske resistenstransgener.
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| US201161548526P | 2011-10-18 | 2011-10-18 | |
| PCT/EP2012/070612 WO2013057164A1 (en) | 2011-10-18 | 2012-10-18 | Production of a human beta cell line from an early post natal pancreas |
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| DK2768948T3 true DK2768948T3 (da) | 2017-08-14 |
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| ES (1) | ES2634457T3 (da) |
| WO (1) | WO2013057164A1 (da) |
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| CN120796168A (zh) | 2013-06-11 | 2025-10-17 | 哈佛学院校长同事会 | SC-β细胞以及用于产生其的组合物和方法 |
| CN107614678B (zh) | 2014-12-18 | 2021-04-30 | 哈佛学院校长同事会 | 干细胞来源的β细胞的产生方法及其使用方法 |
| EP3234110B1 (en) | 2014-12-18 | 2024-02-28 | President and Fellows of Harvard College | METHODS FOR GENERATING STEM CELL-DERIVED ß CELLS AND USES THEREOF |
| WO2016100898A1 (en) | 2014-12-18 | 2016-06-23 | President And Fellows Of Harvard College | Serum-free in vitro directed differentiation protocol for generating stem cell-derived b cells and uses thereof |
| US11629337B2 (en) | 2016-05-11 | 2023-04-18 | Animal Cell Therapy—Act | Production of a canine beta cell line from an immature pancreas |
| EP3710021A4 (en) | 2017-11-15 | 2021-08-11 | Semma Therapeutics, Inc. | ISLAND CELL MANUFACTURING COMPOSITIONS AND METHOD OF USE |
| WO2020033879A1 (en) | 2018-08-10 | 2020-02-13 | Semma Therapeutics, Inc. | Stem cell derived islet differentiation |
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| US6110743A (en) * | 1995-02-10 | 2000-08-29 | The Regents Of The University Of California | Development and use of human pancreatic cell lines |
| US7041634B2 (en) * | 1995-09-27 | 2006-05-09 | Emory University | Method of inhibiting immune system destruction of transplanted viable cells |
| US7745216B2 (en) * | 1999-02-10 | 2010-06-29 | Curis, Inc. | Methods and reagents for treating glucose metabolic disorders |
| EP1103615A1 (en) | 1999-11-25 | 2001-05-30 | Universite De Geneve | Vectors capable of immortalizing non-dividing cells and cells immortalized with said vectors |
| US20050123521A1 (en) * | 2001-06-21 | 2005-06-09 | Regents Of The University Of California | Immortalization of human cells by the ectopic expression of human telomerase reverse transcriptase |
| US20050193432A1 (en) * | 2003-11-18 | 2005-09-01 | Whitehead Institute For Biomedical Research | Xenograft model of functional normal and malignant human breast tissues in rodents and methods thereof |
| WO2008010200A2 (en) | 2006-07-20 | 2008-01-24 | Daniel Farb | Flow deflection devices and method for energy capture machines |
| CA2678870C (en) | 2007-02-21 | 2017-07-11 | Sarl Endocells | Human pancreatic beta cell lines for diagnostic of diabetes |
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- 2012-10-18 ES ES12781298.0T patent/ES2634457T3/es active Active
- 2012-10-18 US US14/352,519 patent/US9493743B2/en active Active
- 2012-10-18 EP EP12781298.0A patent/EP2768948B1/en active Active
- 2012-10-18 WO PCT/EP2012/070612 patent/WO2013057164A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
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| EP2768948A1 (en) | 2014-08-27 |
| US9493743B2 (en) | 2016-11-15 |
| EP2768948B1 (en) | 2017-06-07 |
| WO2013057164A1 (en) | 2013-04-25 |
| ES2634457T3 (es) | 2017-09-27 |
| US20140302155A1 (en) | 2014-10-09 |
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