Non-human mammal model of human degenerative disorder, uses thereof, and method of treating human degenerative disorder

Patent metadata

Field	Value
Publication number	US-9724432-B2
Application number	US-201514701245-A
Country	US
Kind code	B2
Filing date	Apr 30, 2015
Priority date	Apr 30, 2015
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

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.

First claim

What is claimed:

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.

Assignees

• Goldman Steven A
• Univ Rochester

Inventors

• Goldman Steven A

Classifications

• A61K35/30

  Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue · CPC title

• A01K2267/0318

  Animal model for neurodegenerative disease, e.g. non- Alzheimer's · CPC title

• G01N2800/28

  Neurological disorders · CPC title

• A01K67/0271

  Chimeric vertebrates, e.g. comprising exogenous cells · CPC title

• C12N5/06

  Animal cells or tissues; Human cells or tissues (preservation of excised living parts A01N1/10) · CPC title