Diagnostic and therapeutic target for autoimmune diseases and uses thereof
AssigneeThe Regents of the University of Colorado, a body corporate
InventorsJohn C. Hutton, Janet M. Wenzlau, Jan Jensen, Howard Davidson
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Abstract
Described is the identification of ZnT8 as an autoantigen target in type I autoimmune diabetes (T1D), other autoimmune disease, and other diabetes-linked diseases and conditions. Also described are a variety of therapeutic, diagnostic, and prognostic tools and methods based on this discovery. The identification of genetic variation in ZnT8 as an important player in the initiation of the disease process and the progression of autoimmunity to clinical diabetes is disclosed.
Claims95
A fragment of ZnT8, wherein the fragment is selected from the group consisting of, at least the 10 C-terminal amino acids, at least the 25 C-terminal amino acids, at least the 50 C-terminal amino acids, at least the 75 C-terminal amino acids, at least the 100 C-terminal amino acids, at least the 101 C-terminal amino acids, at least the 102 C-terminal amino acids, at least the 104 C-terminal amino acids, and at least the 350 C-terminal amino acids of ZnT8.
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A fragment of ZnT8, comprising, consisting essentially of, or consisting of, at least the amino acid sequence SLTIQMES (positions 346-353 of SEQ ID NO:2).
A fragment of ZnT8, wherein the fragment is selected from the group consisting of, at least the 10 N-terminal amino acids, at least the 25 N-terminal amino acids, at least the 50 N-terminal amino acids, and at least the 74 N-terminal amino acids of ZnT8.
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A fragment of ZnT8, comprising, consisting essentially of, or consisting of, a fragment represented by any one of SEQ ID NOs:
- 8-24 or 40-65.
A chimeric protein, comprising, consisting essentially of, or consisting of, any two or more fragments represented in any of the preceding claims.
A fragment or homologue of ZnT8 comprising at least one epitope of ZnT8 that is selectively bound by an anti-ZnT8 antibody.
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A homologue of ZnT8, comprising a protein that is less than 99% identical to a naturally occurring ZnT8 protein, and that is at least 90% identical to SEQ ID NO:2, and wherein the amino acid at position 325 of SEQ ID NO:2 is selected from the group consisting of arginine, tryptophan and glutamine.
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A method to diagnose an individual who is susceptible to or who is developing an autoimmune disease, comprising detecting antibodies that selectively bind to ZnT8 in a test sample from the individual, wherein detection of increased antibodies in the individual as compared to a negative control, indicates that the individual is susceptible to or is developing the autoimmune disease.
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A method to monitor the progression of type I diabetes autoimmunity in an individual from an initial benign autoreactivity to destructive insulitis, comprising detecting antibodies that selectively bind to ZnT8 in a test sample from the individual, wherein detection of increased antibodies in the individual as compared to a prior measurement of antibodies in the same individual, indicates that the individual is progressing toward destructive insulitis.
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A method to monitor the efficacy of a treatment for preventing type I diabetes, delaying the onset of type I diabetes, or ameliorating autoimmunity in prediabetic individuals, comprising detecting antibodies that selectively bind to ZnT8 in a test sample from the individual, wherein detection of decreased or substantially the same level of antibodies in the individual as compared to a prior measurement of antibodies in the same individual, indicates that the treatment is effective, and wherein detection of increased antibodies in the individual as compared to a prior measurement of antibodies in the same individual indicates that the treatment is not effective.
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Use of ZnT8, a variant thereof, a fragment thereof, a synthetic mimetic thereof, or an antibody that binds to said ZnT8, homologue thereof or fragment thereof, in a diagnostic, prognostic or therapeutic method as described substantially herein.
Dependencies are inferred from the claim text.