Non-human mammal model of human degenerative disorder, uses thereof, and method of treating human degenerative disorder
The present application relates to a non-human mammal model of a human neurodegenerative disorder, methods of producing the non-human mammal model, and methods of using the non-human mammal model to identify agents suitable for treating a neurodegenerative disorder. The present application also relates to methods of treating neurodegenerative disorders and restoring normal brain interstitial potassium levels.
1. A non-human mammal having Huntington's disease wherein at least 30% of all of its glial cells in its corpus callosum are human glial cells and/or at least 5% of all of its glial cells in the white matter of its brain and/or brain stem are human Huntington's disease specific glial cells.
2. The non-human mammal according to claim 1 , wherein the mammal is hypomyelinated.
3. The non-human mammal according to claim 1 , wherein the mammal is normally myelinated.
4. The non-human mammal according to claim 1 , wherein at least 15% of all of the glial cells in the white matter of the mammal's brain and/or brain stem are human Huntington's disease specific glial cells.
5. The non-human mammal according to claim 1 , wherein the white matter is cerebellar white matter and at least 50% of all glial cells in the cerebellar white matter are human Huntington's disease specific glial cells.
6. The non-human mammal according to claim 1 , wherein at least 50% of all of the glial cells in the corpus callosum of the mammal are human Huntington's disease specific glial cells.
7. The non-human mammal according to claim 1 , wherein at least 70% of all of the glial cells in the corpus callosum of the mammal are human Huntington's disease specific glial cells.
8. The non-human mammal according to claim 1 , wherein at least 90% of all of the glial cells in the corpus callosum of the mammal are human Huntington's disease specific glial cells.
9. The non-human mammal according to claim 1 , wherein the human Huntington's disease specific glial cells are derived from a patient having Huntington's disease.
10. The non-human mammal according to claim 1 , wherein the non-human mammal exhibits impaired motor learning compared to a control non-human mammal.
11. The non-human mammal according to claim 1 , wherein striatal neurons of the non-human mammal exhibit increased neuronal excitability and decreased input resistance compared to a control non-human mammal.
12. The non-human mammal according to claim 1 , wherein the human Huntington's disease specific glial cells are derived from human induced pluripotent stem cells.
13. The non-human mammal according to claim 1 , wherein the human Huntington's disease specific glial cells are derived from human embryonic stem cells.
14. The non-human mammal according to claim 1 , wherein the human Huntington's disease specific glial cells are derived from human glial progenitor cells.
15. The non-human mammal according to claim 1 , wherein the human Huntington's disease specific glial cells are derived from human astrocytes.
16. A method of identifying an agent suitable for treating Huntington's disease, said method comprising:
providing the non-human mammal having Huntington's disease of claim 1 ;
providing a candidate agent;
administering the candidate agent to the non-human mammal; and
assessing, as a result of said administering, the therapeutic potential of said candidate agent as suitable for treating Huntington's disease.
17. The method according to claim 16 , wherein at least 15% of all of the glial cells in the white matter of the mammal's brain and/or brain stem are human Huntington's disease specific glial cells.
18. The method according to claim 16 , wherein the white matter of the mammal's brain is cerebellar white matter and at least 50% of all glial cells in the cerebellar white matter of the mammal are human Huntington's disease specific glial cells.
19. The method according to claim 16 , wherein at least 50% of all of the glial cells in the corpus callosum of the mammal are human Huntington's disease specific glial cells.
20. The method according to claim 16 , wherein at least 70% of all of the glial cells in the corpus callosum of the mammal are human Huntington's disease specific glial cells.
21. The method according to claim 16 , wherein the human Huntington's disease specific glial cells are derived from a patient having Huntington's disease.
22. A method of producing a non-human mammal having Huntington's disease, said method comprising:
providing a population of isolated human Huntington's disease specific glial cells;
introducing the population of isolated human Huntington's disease specific glial cells into multiple locations within the forebrain and/or brain stem of the non-human mammal; and
recovering the non-human mammal with human Huntington's disease specific glial cells replacing native glial cells in the brain.
23. The method according to claim 22 , wherein the population of isolated human glial cells is a population of human Huntington's disease specific glial progenitor cells.
24. The method according to claim 22 , wherein at least 30% of the glial cells in the recovered non-human mammal's corpus callosum are human Huntington's disease specific glial cells.
25. The method according to claim 22 , wherein at least 5% of the glial cells in the recovered non-human mammal's white matter of its brain and brain stem are human Huntington's disease specific glial cells.
26. The method according to claim 22 , wherein the mammal is myelin-deficient or myelin-depleted during said introducing.
27. The method according to claim 22 , wherein the human Huntington's disease specific glial cells are derived from a patient having Huntington's disease.