HUMANIZED CHIMERAS FOR THE PROSPECTIVE ASSESSMENT OF CELL ADDITION AND REPLACEMENT THERAPIES

Abstract

A chimeric non-human mammal disease model, wherein (1) at least 30% of all the glial cells in the corpus callosum of the chimeric non-human mammal are human glial cells, and/or (2) at least 5% of all of the glial cells in the white matter of the brain and/or brain stem of the chimeric non-human mammal are human glial cells, and wherein the human glial cells comprise a combination of a first group of human glial cells tagged with a first label and a second group of human glial cells tagged with a second label that is distinguishable from the first label.

Description

Claims

1. A chimeric non-human mammal, wherein (1) at least 30% of all the glial cells in the corpus callosum of the chimeric non-human mammal are human glial cells, and/or (2) at least 5% of all of the glial cells in the white matter of the brain and/or brain stem of the chimeric non-human mammal are human glial cells, and wherein the human glial cells comprise a combination of human disease-specific glial cells and healthy human glial cells, wherein the human disease-specific glial cells are tagged with a first detectable label, and wherein the healthy human glial cells are tagged with a second detectable label that is distinguishable from the first detectable label.

2. The chimeric non-human mammal of claim 1, wherein the human disease-specific glial cells comprise human neurodegenerative disorder-specific glial cells, or human neuropsychiatric disorder-specific glial cells, or human myelin disease-specific glial cells.

3. The chimeric non-human mammal of claim 1, wherein the human disease-specific glial cells comprise human neurodegenerative disorder-specific glial cells and wherein the human neurodegenerative disorder is selected from the group consisting of Huntington’s disease, frontotemporal dementia, Parkinson’s disease, multisystem atrophy, and amyotrophic lateral sclerosis.

4. The chimeric non-human mammal of claim 3, wherein the human disease-specific glial cells comprise Huntington’s disease-specific glial cells.

5. The chimeric non-human mammal of claim 1, wherein the human disease-specific glial cells comprise human neuropsychiatric disorder-specific glial cells and wherein the human neuropsychiatric disorder is selected from the group consisting of schizophrenia, autism spectrum disorder, and bipolar disorder.

6. The chimeric non-human mammal of claim 1, wherein the human disease-specific glial cells comprise human myelin disease-specific glial cells and wherein the human myelin disease leukodystrophy or a white matter disease.

7. The chimeric non-human mammal of claim 1, wherein the mammal is post-natal.

8. The chimeric non-human mammal of claim 1, wherein the mammal is mouse.

9. The chimeric non-human mammal of claim 1, wherein the mammal is immune-incompetent, immune-deficient, or immune-suppressed.

10. The chimeric non-human mammal of claim 1, wherein the human disease-specific glial cells are derived from human disease-specific glial progenitor cells implanted at a first implantation date, wherein the healthy human glial cells are derived from healthy human glial progenitor cells implanted at a second implantation date, and wherein the first implantation date is the same as the second implantation date.

11. The chimeric non-human mammal of claim 1, wherein the human disease-specific glial cells are derived from human disease-specific glial progenitor cells implanted at a first implantation date, wherein the healthy human glial cells are derived from healthy human glial progenitor cells implanted at a second implantation date, and wherein the first implantation date is earlier than the second implantation date.

12. The chimeric non-human mammal of claim 11, wherein the first implantation date is 30-40 weeks earlier than the second implantation date.

13. A chimeric non-human mammal, wherein (1) at least 30% of all the glial cells in the corpus callosum of the chimeric non-human mammal are human glial cells, and/or (2) at least 5% of all of the glial cells in the white matter of the brain and/or brain stem of the chimeric non-human mammal are human glial cells, and wherein the human glial cells comprise a first group of healthy human glial cells tagged with a first detectable label and a second group of healthy human glial cells tagged with a second detectable label that is distinguishable from the first detectable label.

14. The chimeric non-human mammal of claim 13, wherein the first group of healthy human glial cells are derived from a first group of healthy human glial progenitor cells implanted at a first implantation date, wherein the second group of healthy human glial cells are derived from a second group of healthy human glial progenitor cells implanted at a second implantation date, and wherein the first implantation date is the same as the second implantation date.

15. The chimeric non-human mammal of claim 13, wherein the first group of healthy human glial cells are derived from a first group of healthy human glial progenitor cells implanted at a first implantation date, wherein the second group of healthy human glial cells are derived from a second group of healthy human glial progenitor cells implanted at a second implantation date, and wherein the first implantation date is earlier than the second implantation date.

16. The chimeric non-human mammal of claim 15, wherein the first implantation date is 30-40 weeks earlier than the second implantation date.

17. A method for producing a chimeric non-human mammal comprising human glial cells, the method comprises the steps of: introducing a first population of human glial progenitor cells into the brain and/or brain stem of a non-human mammal, wherein the first population of human glial progenitor cells are tagged with a first detectable label;introducing a second population of human glial progenitor cells into the brain and/or brain stem of a non-human mammal, wherein the second population of human glial progenitor cells are tagged with a second detectable label that is distinguishable from the first detectable label;recovering, as a result of said introducing, a chimeric non-human mammal with human glial cells least partially replacing native glial cells in the brain or brain stem, wherein (1) at least 30% of all the glial cells in the corpus callosum of the chimeric non-human mammal are human glial cells, and/or (2) at least 5% of all of the glial cells in the white matter of the brain and/or brain stem of the chimeric non-human mammal are human glial cells.

18. The method of claim 17, wherein the first population of human glial progenitor cells are human disease-specific glial progenitor cells and wherein the second population of human glial progenitor cells are healthy human glial progenitor cells.

19. The method of claim 18, wherein the human disease-specific glial progenitor cells comprise human neurodegenerative disorder-specific glial progenitor cells, or human neuropsychiatric disorder-specific glial progenitor cells, or human myelin disease-specific glial progenitor cells.

20. The method of claim 18, wherein the human disease-specific glial progenitor cells comprise Huntington’s disease-specific glial progenitor cells.