Mouse model of DITRA disease and uses thereof
AssigneeRegeneran Pharmaceuticals, Inc.
InventorsAndrew J. Murphy, Alexander O. Mujica, Ka-Man Venus Lai, Sokol Haxhinasto
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Abstract
This disclosure relates to genetically modified rodent animals and rodent models of human diseases. More specifically, this disclosure relates to genetically modified rodents whose genome comprises a humanized Il1rl2 gene (coding for the IL1rl2 subunit of the IL-36R protein) and human IL-36α, β and γ ligand genes. The genetically modified rodents disclosed herein display enhanced skin and intestinal inflammation as a preclinical model of psoriasis and IBD, respectively, and serve as a rodent model of human DITRA disease.
Claims27
A genetically modified mouse whose genome comprises:
- (1) a humanized interleukin-1 receptor-like 2 (Il1rl2) gene, wherein the humanized Il1rl2 gene
- (i) encodes a humanized Il1rl2 protein that comprises the ectodomain of a human IL1RL2 protein and the transmembrane-cytoplasmic domains of a mouse Il1rl2 protein;
- (ii) results from a replacement of a genomic fragment of an endogenous mouse Il1rl2 gene encoding the ectodomain of an endogenous mouse Il1rl2 protein with a nucleotide sequence of a human IL1RL2 gene encoding the ectodomain of the humanized Il1rl2 protein;
- and
- (iii) is operably linked to the endogenous mouse Il1rl2 promoter;
- (2) a human interleukin-1 family member 6 (IL1F6) gene, which replaces the endogenous mouse Il1f6 gene;
- (3) a human interleukin-1 family member 8 (IL1F8) gene, which replaces the endogenous mouse Il1f8 gene;
- and
- (4) a human interleukin-1 family member 9 (Il1F9) gene, which replaces the endogenous mouse Ilf9 gene;
- wherein the mouse expresses the humanized Il1rl2 protein, human IL1F6, human IL1F8, and human IL1F9.
A method of making a genetically modified mouse, comprising
- (A) modifying a mouse genome to comprise
- (1) a humanized interleukin-1 receptor-like 2 (IL1rl2) gene which
- (i) encodes a humanized IL1r12 protein that comprises the ectodomain of a human IL1RL2 protein and the transmembrane-cytoplasmic domains of a mouse Illr12 protein;
- (ii) results from a replacement of a genomic fragment of an endogenous mouse Il1r12 gene encoding the ectodomain of an endogenous mouse Il1r12 protein with a nucleotide sequence of a human IL1RL2 gene encoding the ectodomain of the humanized ILlr12 protein;
- and
- (iii) is operably linked to the endogenous mouse Il1r12 promoter;
- (2) a human interleukin-1 family member 6 (IL1F6) gene, which replaces the endogenous mouse Il1f6 gene;
- (3) a human interleukin-1 family member 8 (IL1F8) gene, which replaces the endogenous mouse Il1f8 gene;
- and
- (4) a human interleukin-1 family member 9 (IL1F9) gene, which replaces the endogenous mouse Il1f9 gene;
- and
- (B) making a genetically modified mouse comprising the modified genome, wherein the mouse expresses the humanized Il1rl2 protein, human IL1F6, human IL1F8, and human IL1F9.
An isolated mouse embryonic stem (ES) cell whose genome comprises:
- (1) a humanized interleukin-1 receptor-like 2 (Il1rl2) gene, wherein the humanized Il1rl2 gene
- (i) encodes a humanized Il1rl2 protein that comprises the ectodomain of a human IL1RL2 protein and the transmembrane-cytoplasmic domains of a mouse Il1rl2 protein;
- (ii) results from a replacement of a genomic fragment of an endogenous mouse Il1rl2 gene encoding the ectodomain of an endogenous mouse Il1rl2 protein with a nucleotide sequence of a human IL1RL2 gene encoding the ectodomain of the humanized Il1rl2 protein;
- and
- (iii) is operably linked to the endogenous mouse Il1rl2 promoter;
- (2) a human interleukin-1 family member 6 (IL1F6) gene, which replaces the endogenous mouse Il1f6 gene;
- (3) a human interleukin-1 family member 8 (IL1F8) gene, which replaces the endogenous mouse Ilf8 gene;
- and
- (4) a human interleukin-1 family member 9 (IL1F9) gene, which replaces the endogenous mouse Ilf9 gene.
Dependencies are inferred from the claim text.