	US 12,402,611 B2
	Genetically modified mice and engraftment
Sean Stevens, Del Mar, CA (US); Andrew J. Murphy, Croton-on-Hudson, NY (US); Richard Flavell, Guilford, CT (US); Elizabeth Eynon, New Haven, CT (US); Jorge Galan, New Haven, CT (US); Tim Willinger, Ultran (SE); Markus Manz, Zurich (CH); Anthony Rongvaux, New Haven, CT (US); and George D. Yancopoulos, Yorktown Heights, NY (US)
Assigned to Regeneron Pharmaceuticals, Inc., Tarrytown, NY (US)
Filed by Regeneron Pharmaceuticals, Inc., Tarrytown, NY (US); Yale University, New Haven, CT (US); and Institute for Research in Biomedicine (IRB), Bellinzona (CH)
Filed on Jun. 9, 2021, as Appl. No. 17/343,294.
Application 17/343,294 is a continuation of application No. 16/352,674, filed on Mar. 13, 2019, granted, now 11,051,499.
Application 16/352,674 is a continuation of application No. 15/397,628, filed on Jan. 3, 2017, granted, now 10,278,374, issued on May 7, 2019.
Application 15/397,628 is a continuation of application No. 14/053,182, filed on Oct. 14, 2013, granted, now 9,554,563, issued on Jan. 31, 2017.
Application 14/053,182 is a continuation of application No. 13/617,448, filed on Sep. 14, 2012, granted, now 9,301,509, issued on Apr. 5, 2016.
Application 13/617,448 is a continuation of application No. 12/897,517, filed on Oct. 4, 2010, granted, now 8,541,646, issued on Sep. 24, 2013.
Claims priority of provisional application 61/249,069, filed on Oct. 6, 2009.
Claims priority of provisional application 61/256,237, filed on Oct. 29, 2009.
Claims priority of provisional application 61/320,132, filed on Apr. 1, 2010.
Prior Publication US 2022/0000084 A1, Jan. 6, 2022
Int. Cl. A01K 67/0278 (2024.01); A01K 67/0271 (2024.01); A01K 67/0275 (2024.01); A61K 49/00 (2006.01); C07K 14/52 (2006.01); C07K 14/535 (2006.01); C07K 14/54 (2006.01); C07K 14/715 (2006.01); C12N 9/00 (2006.01)

CPC A01K 67/0278 (2013.01) [A01K 67/0271 (2013.01); A01K 67/0275 (2013.01); A61K 49/00 (2013.01); C07K 14/524 (2013.01); C07K 14/535 (2013.01); C07K 14/5403 (2013.01); C07K 14/7155 (2013.01); C12N 9/00 (2013.01); A01K 2207/12 (2013.01); A01K 2207/15 (2013.01); A01K 2217/072 (2013.01); A01K 2217/075 (2013.01); A01K 2217/15 (2013.01); A01K 2227/105 (2013.01); A01K 2267/03 (2013.01); A01K 2267/0331 (2013.01); A01K 2267/0337 (2013.01); A01K 2267/0381 (2013.01); A01K 2267/0387 (2013.01)]

8 Claims

1. A method comprising:

engrafting a second mouse with human CD34⁺ hematopoietic cells isolated from a genetically modified first mouse, wherein each of the first mouse and the second mouse are null for a recombination-activating gene 2 (RAG2) gene and null for a mouse interleukin 2 receptor gamma (IL-2Rg) gene, wherein the genetically modified first mouse comprises an engraftment of human CD34⁺hematopoietic cells and a replacement of each allele of the mouse thrombopoietin (TPO) gene with a human TPO gene at the mouse TPO gene locus, wherein the genetically modified first mouse does not express mouse TPO, and wherein the engraftment of human CD34⁺hematopoietic cells isolated from the genetically modified first mouse results in a statistically significant increase in human CD45⁺hematopoietic cells in the bone marrow of the second mouse relative to human CD45⁺hematopoietic cells in a RAG2-null IL-2Rg-null fourth mouse engrafted with human CD34⁺hematopoietic cells isolated from a RAG2-null IL-2Rg-null third mouse, wherein the RAG2-null IL-2Rg-null third mouse comprises an engraftment of human CD34⁺hematopoietic cells and expresses mouse TPO.