Genetically modified rat comprising a cytokine gene disruption and exhibiting a greater susceptibility to a cytokine-mediated autoimmune and/or inflammatory disease
DCFirst Claim
1. A genetically modified rat or progeny of the rat, wherein the rat or its progeny comprise in at least some of its cells a genome comprising a disruption of one or more cytokine genes that results in the misexpression of the one or more cytokine genes, wherein the rat or its progeny exhibits a greater susceptibility to a cytokine-mediated autoimmune and/or inflammatory disease than a rat or progeny rat not comprising the genetic mutation.
1 Assignment
Litigations
1 Petition
Reexamination
Accused Products
Abstract
The present invention relates to the engineering of animal cells, preferably mammalian, more preferably rat, that are deficient due to the disruption of gene(s) or gene product(s) resulting in cytokine-cytokine mediated autoimmune and inflammatory disease. In another aspect, the invention relates to genetically modified rats, as well as the descendants and ancestors of such animals, which are animal models of human autoimmune and inflammatory disease and methods of their use. Specifically, the invention pertains to a genetically altered rat, or a rat cell in culture, that is defective in at least one of two alleles of a cytokine gene such as the Faslg gene, the Fas gene, etc. In one embodiment, the cytokine gene is the Faslg gene. In another embodiment, the cytokine gene is one of several known cytokine genes, such as Fas, IFNγ, TNF-α, IL-2, IL-10, and IL-12. The inactivation of at least one of these cytokine alleles results in an animal with a higher susceptibility to cytokine-cytokine mediated autoimmune and inflammatory disease induction. In one embodiment, the genetically altered animal is a rat of this type and is able to serve as a useful model for cytokine-cytokine mediated autoimmune and inflammatory disease and as a test animal for autoimmune and other studies.
27 Citations
47 Claims
- 1. A genetically modified rat or progeny of the rat, wherein the rat or its progeny comprise in at least some of its cells a genome comprising a disruption of one or more cytokine genes that results in the misexpression of the one or more cytokine genes, wherein the rat or its progeny exhibits a greater susceptibility to a cytokine-mediated autoimmune and/or inflammatory disease than a rat or progeny rat not comprising the genetic mutation.
- 11. A genetically modified rat or progeny of the rat, wherein the rat or its progeny comprise in at least some of its cells a genome comprising a disruption of one or more cytokine genes that results in the rat or its progeny exhibiting a greater susceptibility to a cytokine-mediated autoimmune and/or inflammatory disease than a rat or progeny rat not comprising the genetic mutation.
-
24. A method for determining whether a compound is potentially useful for treating or alleviating the symptoms of a cytokine gene disorder comprising
(a) providing an isolated genetically modified rat cell comprising a genome comprising a disruption of one or more cytokine genes that causes the one or more cytokine genes to be misexpressed, wherein the rat exhibits a greater susceptibility to a cytokine-mediated autoimmune and/or inflammatory disease than a rat not comprising the genetic mutation, (b) contacting the cell with a compound, and (c) monitoring the activity of the cytokine protein, such that a change in activity in response to the compound indicates that the compound is potentially useful for treating or alleviating the symptoms of a cytokine gene disorder.
-
26. A screening method for identifying useful compounds, comprising
(a) providing an assay system comprising a rat model system comprising a genetically modified rat or progeny of the rat, wherein the rat or its progeny comprise in at least some of its cells a genome comprising a disruption of one or more cytokine genes that results in the misexpression of the one or more cytokine genes, wherein the rat or its progeny exhibits a greater susceptibility to a cytokine-mediated autoimmune and/or inflammatory disease than a rat or progeny rat not comprising the genetic mutation; -
(b) contacting the model system with a candidate test agent; and (c) detecting a phenotypic change in the model system that indicates that the cytokine function is restored when compared relative to wild-type cells. - View Dependent Claims (27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 46)
-
-
39. A screening method for identifying useful compounds, comprising
(a) providing an assay system comprising a model system comprising a genetically modified rat at least some of whose cells comprise a genome comprising a disruption of one or more cytokine genes that causes the one or more cytokine genes to be misexpressed, wherein the rat exhibits a greater susceptibility to a cytokine-mediated autoimmune and/or inflammatory disease than a rat not comprising the genetic mutation; -
(b) contacting the model system with a candidate test agent; and (c) detecting a change in cytokine polypeptide expression or activity between the presence and absence of the candidate test agent that indicates the presence of a candidate modulating agent. - View Dependent Claims (40, 41, 42, 43, 44, 45)
-
Specification