IP Library › Granted Patent US 12,653,168
Granted Patent B2
US 12,653,168 · App. 17/275,096 · Granted Jun 16, 2026

Complement factor H gene knockout rat as a model of C3 glomerulopathy

Inventors: Kishor Devalaraja-Narashimha (Yorktown Heights, NY); Jeffrey D. Lee (New York, NY); Lori Morton (Chappaqua, NY)
Assignee: REGENERON PHARMACEUTICALS, INC.
A01K67/0276A01K2217/075A01K2227/105A01K2267/035A01K2267/0393
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Quick Facts
Patent No.
US 12,653,168
App. No.
17/275,096
Granted
Jun 16, 2026
Kind
B2
Abstract

Rat cells and rats comprising an inactivated Cfh locus and methods of making and using such rat cells and rats are provided. The rats comprising an inactivated Cfh locus model C3 glomerulopathy (C3G). Methods are provided for using such rats comprising an inactivated Cfh locus to assess in vivo efficacy of putative C3G therapeutic agents.

Claims (39)

1 . A genetically modified rat with a modification consisting of an inactivated endogenous Cfh locus, wherein the genetically modified rat is homozygous for the inactivated endogenous Cfh locus, wherein the genetically modified rat has one or more symptoms of C3 glomerulopathy (C3G),

wherein the genetically modified rat has increased blood urea nitrogen levels at an age of between about 7 weeks and about 17 weeks compared to a wild type rat at an age of between about 7 weeks and about 17 weeks,

wherein the genetically modified rat has a decreased lifespan compared to a wild type rat, and

wherein the median lifespan of the genetically modified rat is less than 150 days.

2 . The genetically modified rat of claim 1 , wherein the start codon of the endogenous Cfh locus is mutated or deleted in the inactivated endogenous Cfh locus.

3 . The genetically modified rat of claim 2 , wherein the start codon of the endogenous Cfh locus is deleted in the inactivated endogenous Cfh locus.

4 . The genetically modified rat of claim 3 , wherein the coding sequence in the first exon in the endogenous Cfh locus is deleted in the inactivated endogenous Cfh locus.

5 . The genetically modified rat of claim 4 , wherein the splice donor site in the first intron in the endogenous Cfh locus is deleted in the inactivated endogenous Cfh locus.

6 . The genetically modified rat of claim 1 , wherein the rat is a male.

7 . The genetically modified rat of claim 1 , wherein the rat is a female.

8 . The genetically modified rat of claim 1 , wherein the genetically modified rat has decreased circulatory C3 levels compared to a wild type rat.

9 . The genetically modified rat of claim 8 , wherein the circulatory C3 levels are less than 200 μg/mL.

10 . The genetically modified rat of claim 9 , wherein the circulatory C3 levels are less than 100 μg/mL.

11 . The genetically modified rat of claim 8 , wherein the genetically modified rat has decreased circulatory C3 levels at an age of between about 7 weeks and about 17 weeks compared to the wild type rat at an age of between about 7 weeks and about 17 weeks.

12 . The genetically modified rat of claim 1 , wherein the genetically modified rat has increased serum cystatin C levels or increased urinary albumin levels compared to a wild type rat.

13 . The genetically modified rat of claim 12 , wherein the genetically modified rat has increased serum cystatin C levels and increased urinary albumin levels compared to a wild type rat.

14 . The genetically modified rat of claim 1 , wherein the blood urea nitrogen levels are more than 10, more than 20, more than 30, more than 40, more than 50, more than 60, more than 70, more than 80, more than 90, or more than 100 mg/dL.

15 . The genetically modified rat of claim 12 , wherein the serum cystatin C levels are more than 1000, more than 1100, more than 1200, more than 1300, more than 1400, more than 1500, more than 1600, more than 1700, more than 1800, more than 1900, or more than 2000 ng/mL.

16 . The genetically modified rat of claim 12 , wherein:

(I) the urinary albumin per day is more than 1000, more than 2000, more than 3000, more than 4000, more than 5000, more than 6000, more than 7000, more than 8000, more than 9000, or more than 10000 μg/day; and/or

(II) the ratio of urinary albumin to urinary creatinine is more than 100, more than 200, more than 300, more than 400, more than 500, more than 600, more than 700, more than 800, more than 900, more than 1000, more than 1100, more than 1200, more than 1300, more than 1400, more than 1500, more than 1600, more than 1700, more than 1800, more than 1900, or more than 2000 μg:mg.

17 . The genetically modified rat of claim 12 , wherein the genetically modified rat has increased serum cystatin C levels at an age of between about 7 weeks and about 17 weeks or increased urinary albumin levels at an age of between about 7 weeks and about 17 weeks compared to the wild type rat at an age of between about 7 weeks and about 17 weeks.

18 . The genetically modified rat of claim 1 , wherein the genetically modified rat has increased C3 deposition in the kidneys compared to a wild type rat.

19 . The genetically modified rat of claim 18 , wherein the genetically modified rat has increased C3 deposition in the kidneys at an age of between about 7 weeks and about 17 weeks compared to the wild type rat at an age of between about 7 weeks and about 17 weeks.

20 . The genetically modified rat of claim 1 , wherein the genetically modified rat has increased C5b-9 deposition in the kidneys compared to a wild type rat.

21 . The genetically modified rat of claim 20 , wherein the genetically modified rat has increased C5b-9 deposition in the kidneys at an age of between about 7 weeks and about 17 weeks compared to the wild type rat at an age of between about 7 weeks and about 17 weeks.

22 . The genetically modified rat of claim 1 , wherein the genetically modified rat has increased glomerular pathology compared to a wild type rat.

23 . The genetically modified rat of claim 22 , wherein the increased glomerular pathology comprises increased glomerular basement membrane thickness, increased podocyte foot process width, or decreased podocyte foot process number compared to the wild type rat.

24 . The genetically modified rat of claim 23 , wherein the increased glomerular pathology comprises increased glomerular basement membrane thickness, increased podocyte foot process width, and decreased podocyte foot process number compared to the wild type rat.

25 . The genetically modified rat of claim 23 , wherein:

(I) the increase in glomerular basement membrane thickness is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold compared to the wild type rat; and/or

(II) the average glomerular basement membrane thickness in glomeruli in the genetically modified rat is at least 0.2, at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, or at least 1.8 microns.

26 . The genetically modified rat of claim 23 , wherein:

(I) the increase in podocyte foot process width is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, or at least 7-fold compared to the wild type rat; and/or

(II) the average width of podocyte foot process in glomeruli in the genetically modified rat is at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.5, at least 2.0, or at least 2.5 microns.

27 . The genetically modified rat of claim 23 , wherein:

(I) the decrease in podocyte foot process number is at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, or at least 3.8-fold compared to the wild type rat; and/or

(II) the average podocyte foot process number per micron length in the genetically modified rat is less than 2.5, less than 2, less than 1.5, less than 1, less than 0.9, or less than 0.8.

28 . The genetically modified rat of claim 22 , wherein the genetically modified rat has increased glomerular pathology at an age of between about 7 weeks and about 17 weeks compared to the wild type rat at an age of between about 7 weeks and about 17 weeks.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 24, 2025
From: DEVALARAJA-NARASHIMHA, KISHOR; LEE, JEFFREY D.; MORTON, LORI
To: REGENERON PHARMACEUTICALS, INC.
Reel/Frame 070940/0308 →
Continuity (2)
Provisional Application 62730690 · Sep 13, 2018
Related Publication 20220053741A1 · Feb 24, 2022
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