DK2134846T3 - Transgent svin som model for Alzheimers sygdom - Google Patents
Transgent svin som model for Alzheimers sygdom Download PDFInfo
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- DK2134846T3 DK2134846T3 DK08715608.9T DK08715608T DK2134846T3 DK 2134846 T3 DK2134846 T3 DK 2134846T3 DK 08715608 T DK08715608 T DK 08715608T DK 2134846 T3 DK2134846 T3 DK 2134846T3
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Claims (15)
1. Genetisk modificeret gris som en model til undersøgelse af Alzheimers sygdom, hvor grisemodellen udtrykker mindst én fænotype forbundet med sygdommen og omfatter mindst ét modificeret a. humant APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller b. humant PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller c. porcint APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller d. porcint PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller e. humant APP-gen eller en del deraf omfattende en svensk mutation og/eller f. humant APP-gen eller en del deraf, som er APPsw695-genet, og/eller g. humant PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, og/eller h. humant APP-gen eller en del deraf omfattende en svensk mutation og mindst ét modificeret PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, og/eller i. humant APP-gen eller en del deraf, som er APPsw695-genet, og mindst ét modificeret PS 1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation.
2. Modificeret gris ifølge krav 1, hvor grisen er en minigris.
3. Modificeret gris ifølge krav 1, hvor det mindst ene modificerede APP-gen eller en del deraf er mindst ét modificeret humant APP-gen eller en del deraf omfattende en svensk mutation, og hvor det mindst ene modificerede PS1-gen eller en del deraf er mindst ét modificeret humant PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation.
4. Modificeret gris ifølge krav 3, hvor det mindst ene modificerede APP-gen eller en del deraf er APP695sw, og hvor det mindst ene modificerede PS1 -gen eller en del deraf er mindst ét modificeret humant PS1-gen eller en del deraf omfattende en mutation, der koder for et PS1-protein, der indeholder en Pro117Leu-mutation.
5. Genetisk modificeret griseblastocyst afledt af den genetisk modificerede grisemodel som defineret i krav 1, hvor nævnte modificerede griseblastocyst omfatter mindst ét modificeret a. humant APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller b. humant PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller c. porcint APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller d. porcint PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller e. humant APP-gen eller en del deraf omfattende en svensk mutation og/eller f. humant APP-gen eller en del deraf, som er APPsw695-genet, og/eller g. humant PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, og/eller h. humant APP-gen eller en del deraf omfattende en svensk mutation og mindst ét modificeret PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, og/eller i. humant APP-gen eller en del deraf, som er APPsw695-genet, og mindst ét modificeret PS 1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation.
6. Genetisk modificeret griseembryo afledt af den genetisk modificerede grisemodel som defineret i krav 1, idet nævnte embryo omfatter mindst ét modificeret a. humant APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller b. humant PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller c. porcint APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller d. porcint PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller e. humant APP-gen eller en del deraf omfattende en svensk mutation og/eller f. humant APP-gen eller en del deraf, som er APPsw695-genet, og/eller g. humant PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, og/eller h. humant APP-gen eller en del deraf omfattende en svensk mutation og mindst ét modificeret PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, og/eller i. humant APP-gen eller en del deraf, som er APPsw695-genet, og mindst ét modificeret PS 1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation.
7. Genetisk modificeret griseføtus afledt af den genetisk modificerede grisemodel som defineret i krav 1, idet nævnte griseføtus omfatter mindst ét modificeret a. humant APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller b. humant PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller c. porcint APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller d. porcint PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller e. humant APP-gen eller en del deraf omfattende en svensk mutation og/eller f. humant APP-gen eller en del deraf, som er APPsw695-genet, og/eller g. humant PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, og/eller h. humant APP-gen eller en del deraf omfattende en svensk mutation og mindst ét modificeret PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, og/eller i. humant APP-gen eller en del deraf, som er APPsw695-genet, og mindst ét modificeret PS 1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation.
8. Genetisk modificeret donorcelle og/eller cellekerne afledt af den genetisk modificerede grisemodel som defineret i krav 1, idet donorcellen og/eller cellekernen omfatter mindst ét modificeret a. humant APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller b. humant PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller c. porcint APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller d. porcint PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller e. humant APP-gen eller en del deraf omfattende en svensk mutation og/eller f. humant APP-gen eller en del deraf, som er APPsw695-genet, og/eller g. humant PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholderen Pro117Leu-mutation, og/eller h. humant APP-gen eller en del deraf omfattende en svensk mutation og mindst ét modificeret PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, og/eller i. humant APP-gen eller en del deraf, som er APPsw695-genet, og mindst ét modificeret PS 1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation.
9. Modificeret gris ifølge et hvilket som helst af de foregående krav, hvor den mindst ene fænotype er mindst 10% reduceret lugtesans i sammenligning med et standardniveau for lugtesans observeret for grisen.
10. Modificeret gris ifølge et hvilket som helst af de foregående krav, hvor den mindst ene fænotype er mindst 10% reduceret semantisk hukommelse sammenlignet med et standardniveau for semantisk hukommelse observeret for grisen.
11. Modificeret gris ifølge et hvilket som helst af de foregående krav, hvor den mindst ene fænotype er mindst 10% reduceret visuel-rumlig hukommelse sammenlignet med standardniveauet for visuel-rumlig hukommelse observeret for grisen.
12. Modificeret gris ifølge et hvilket som helst af de foregående krav, hvor den mindst ene fænotype er akkumulering af abeta-protein og/eller tau-protein.
13. Genetisk modificeret grisemodel, griseblastocyst, embryo, føtus og/eller donorcelle ifølge et hvilket som helst af kravene 1 til 12, der kan opnås ved kerneoverførsel omfattende trinnene i) etablering af mindst én griseoocyt med i det mindste en del af en modificeret zona pellucida, ii) adskillelse af oocyten i mindst to dele, hvilket tilvejebringer en oocyt, der har en kerne og mindst én cytoplast, iii) etablering af en grisedonorcelle eller cellekerne omfattende mindst ét modificeret a. humant APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller b. humant PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller c. porcint APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 og/eller d. porcint PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og/eller e. humant APP-gen eller en del deraf omfattende en svensk mutation og/eller f. humant APP-gen eller en del deraf, som er APPsw695-genet, og/eller g. humant PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, og/eller h. humant APP-gen eller en del deraf omfattende en svensk mutation og mindst ét modificeret PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, og/eller i. humant APP-gen eller en del deraf, som er APPsw695-genet, og mindst ét modificeret PS1-gen eller en del deraf omfattende en mutation, som koder for et PS1-protein, der indeholder en Pro117Leu-mutation, iv) fusion af den mindst ene cytoplast med donorcellen eller den membranomsluttede cellekerne, v) opnåelse af et rekonstrueret embryo, vi) aktivering af det rekonstruerede embryo til dannelse af et embryo; dyrkning af embryoet; og vii) overførsel af det dyrkede embryo til en værtsgris, således at embryoet udvikler sig til et genetisk modificeret føtus, hvor det genetisk modificerede embryo kan opnås ved trin i) til v) og eventuelt vi), hvor den genetisk modificerede blastocyst kan opnås ved trin i) til vi) og eventuelt vii), hvor det genetisk modificerede føtus kan opnås ved trin i) til vii).
14. Fremgangsmåde til evaluering af virkningen afen terapeutisk behandling af Alzheimers sygdom, hvilken fremgangsmåde omfatter trinnene i) tilvejebringelse af grisemodellen ifølge et hvilket som helst af kravene 1 til 13, ii) behandling af grisemodellen med et farmaceutisk præparat, der udøver en virkning på fænotypen, og iii) evaluering af den observerede virkning.
15. Fremgangsmåde til screening af virkningen af et farmaceutisk præparat mod Alzheimers sygdom, hvilken fremgangsmåde omfatter trinnene i) tilvejebringelse af grisemodellen ifølge et hvilket som helst af kravene 1 til 13, ii) idet grisemodellen udtrykker mindst ét modificeret humant APP-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 1 eller mindst ét modificeret humant PS1-gen eller en del deraf omfattende mindst én mutation valgt fra tabel 2 og den nævnte fænotype for nævnte sygdom, iii) administration til grisemodellen af et farmaceutisk præparat, hvis effektivitet skal evalueres, og iv) evaluering af det farmaceutiske præparats eventuelle virkning på den fænotype, der udøves af det mindst ene modificerede humane APP-gen eller en del deraf eller det mindst ene modificerede humane PS1-gen eller en del deraf.
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PCT/DK2008/050054 WO2008106981A1 (en) | 2007-03-07 | 2008-03-06 | Transgenic pig as a model of alzheimer's disease |
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US8912386B2 (en) | 2007-03-28 | 2014-12-16 | University Of Iowa Research Foundation | Transgenic pig model of cystic fibrosis |
US8618352B2 (en) | 2007-03-28 | 2013-12-31 | University Of Iowa Research Foundation | Transgenic porcine models of cystic fibrosis |
WO2008121199A2 (en) * | 2007-03-28 | 2008-10-09 | University Of Iowa Research Foundation | Transgenic animal models of disease |
KR101791296B1 (ko) * | 2014-04-17 | 2017-10-27 | 제주대학교 산학협력단 | 알츠하이머병 관련 돌연변이 유전자를 포함하는 발현 카세트, 벡터, 및 이를 이용하여 형질전환된 세포주 |
EP3140403A4 (en) * | 2014-05-09 | 2017-12-20 | Université Laval | Prevention and treatment of alzheimer's disease by genome editing using the crispr/cas system |
KR102656470B1 (ko) | 2014-12-10 | 2024-04-09 | 리전츠 오브 더 유니버스티 오브 미네소타 | 질환을 치료하기 위한 유전적으로 변형된 세포, 조직 및 장기 |
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WO1996040896A1 (en) | 1995-06-07 | 1996-12-19 | Athena Neurosciences, Inc. | Method for identifying alzheimer's disease therapeutics using transgenic animal models |
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