Mouse model for engraftment potential
View Patent ↗Disclosed herein is the generation of a permissive murine strain (NSGW) that exhibits enhanced levels of human chimerism without pre-conditioning.
1. A mouse whose genome comprises: (i) a homozygous non-obese diabetic (NOD) polymorphism of a Sirpa gene; (ii) a homozygous scid mutation of a Prkdc gene, wherein the homozygous scid mutation of the Prkdc gene is a T to A transversion at codon 4095, wherein the T to A transversion at codon 4095 creates a premature stop codon; (iii) a homozygous disruption of a Il2rγ gene, wherein the disruption causes the ablation of Il2rγ protein expression; and (iv) a homozygous W41 mutation of a Kit gene, wherein the homozygous W41 mutation of the Kit gene is a V to M substitution at residue 831 of the c-Kit gene, wherein said mouse tolerates xenogeneic hematopoietic stem cell transplantation without the need for irradiation prior to said transplantation.
2. The mouse of claim 1 , further comprising a homozygous genotype at nucleotide 291 of a Tyrosinase gene, wherein the homozygous genotype is a G at nucleotide 291 of the Tyrosinase gene.
3. The mouse of claim 2 , wherein the mouse is not albino.
4. The mouse of claim 1 , wherein the mouse is immunodeficient.
5. The mouse of claim 1 , wherein the mouse has a C57BL/6J genetic background.
6. The mouse of claim 1 , wherein the homozygous disruption of the Il2rγ gene is further defined as a homozygous replacement of part of exon 3 and all of exons 4-8 of the Il2rγ gene with a neomycin resistance cassette.
7. The mouse of claim 1 , further comprising xenogeneic hematopoietic stem cells.
8. The mouse of claim 7 , wherein the xenogeneic hematopoietic stem cells are human hematopoietic stem cells.
9. The mouse of claim 8 , wherein the human hematopoietic stem cells are CD34+ umbilical cord blood-derived cells.
10. A method of xenogeneic hematopoietic cell engraftment in a mouse according to claim 1 , comprising administering xenogeneic hematopoietic cells to the mouse absence of irradiation of the mouse.
11. The method of claim 10 , wherein the mouse is not irradiated prior to administering the xenogeneic stem cells.
12. A method of claim 10 , wherein the xenogeneic hematopoietic cells are xenogeneic hematopoietic stem cells.
13. The method of claim 12 , wherein the xenogeneic hematopoietic stem cells are human hematopoietic stem cells.
14. The method of claim 13 , wherein the human hematopoietic stem cells are CD34+ umbilical cord blood-derived cells.
15. The method of claim 13 , wherein the engraftment level of human CD45+ cells in the bone marrow of the mouse is 80% or more.
16. The method of claim 15 , wherein the engraftment level of human CD45+ cells in the bone marrow of the mouse is 90% or more.
17. The method of claim 13 , wherein the engraftment level of human CD45+ cells in the spleen of the mouse is 80% or more.