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US 2018/0020647 A1Published application
Genetically Modified Non-Human Animals And Methods Of Use Thereof
AssigneesRegeneron Pharmaceuticals, Inc., Yale University, Institute for Research in Biomedicine (IRB)
InventorsRichard Flavell, Markus Manz, Anthony Rongvaux, Till Strowig, Tim Willinger, Andrew J. Murphy, Sean Stevens, George Yancopoulos
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Abstract
The invention relates generally to genetically modified non-human animals expressing human polypeptides and their methods of use.
Claims14
A genetically modified mouse comprising in its genome:
- a recombination activating gene 2 (Rag-2) gene knock-out;
- an IL2 receptor gamma chain (IL2rg) gene knock-out;
- a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide, wherein the nucleic acid encoding the human M-CSF polypeptide is operably linked to a M-CSF promoter at a mouse M-CSF gene locus;
- a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide, wherein the nucleic acid encoding the human IL-3 polypeptide is operably linked to a IL-3 promoter at a mouse IL-3 gene locus;
- a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide, wherein the nucleic acid encoding the human GM-CSF polypeptide is operably linked to a GM-CSF promoter at a mouse GM-CSF gene locus;
- a replacement of a mouse-SIRPA gene with a nucleic acid encoding a fusion protein comprising a biologically active fragment of a full length human SIRPA polypeptide, wherein the nucleic acid encoding the fusion protein is operably linked to a SIRPA promoter;
- and
- a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide, wherein the nucleic acid encoding the human TPO polypeptide is operably linked to a TPO promoter at a mouse TPO gene locus, wherein the mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the fusion protein, and the human TPO polypeptide.
5 more elements
-8. (canceled)
A method of hematopoietic stem and progenitor cell (HSPC) engraftment in a genetically modified mouse, the method comprising the step of:
- administering at least one HSPC to the genetically modified mouse, wherein the genetically modified mouse comprises in its genome:
- a recombination activating gene 2 (Rag-2) gene knock-out;
- an IL2 receptor gamma chain (IL2rg) gene knock-out;
- a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide, wherein the nucleic acid encoding the human M-CSF polypeptide is operably linked to a M-CSF promoter at a mouse M-CSF gene locus;
- a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide, wherein the nucleic acid encoding the human IL-3 polypeptide is operably linked to a IL-3 promoter at a mouse IL-3 gene locus;
- a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide, wherein the nucleic acid encoding the human GM-CSF polypeptide is operably linked to a GM-CSF promoter at a mouse GM-CSF gene locus;
- a replacement of a mouse-SIRPA gene with a nucleic acid encoding a fusion protein comprising a biologically active fragment of a full length human SIRPA polypeptide, wherein the nucleic acid encoding the fusion protein is operably linked to a SIRPA promoter;
- and
- a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide, wherein the nucleic acid encoding the human TPO polypeptide is operably linked to a TPO promoter at a mouse TPO gene locus, wherein the mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the fusion protein, and the human TPO polypeptide.
6 more elements
-18. (canceled)
-27. (canceled)
Dependencies are inferred from the claim text.