Methods for determining and inhibiting rheumatoid arthritis associated with the BRAF oncogene in a subject
Inventors
Assignees
US Department of Veterans Affairs • Government of the United States of America
Publication Number
US-9133460-B2
Publication Date
2015-09-15
Expiration Date
2032-04-05
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Abstract
The invention provides methods for determining whether a subject is suffering from a rheumatoid arthritis associated with the BRAF oncogene comprising contacting isolated fibroblasts from the subject with a molecule or pool of molecules directed to the BRAF oncogene; and culturing the sample in the presence of the agent and determining whether BRAF oncogene expression by the cell is decreased and/or whether cells in the sample return to a less transformed phenotype, exhibit decreased cell proliferation and/or exhibit increased contact inhibition, any of which is indicative that the subject is suffering from a rheumatoid arthritis associated with the BRAF oncogene.
Core Innovation
The invention provides methods for determining whether a subject is suffering from a rheumatoid arthritis associated with the BRAF oncogene. This involves contacting isolated fibroblasts from the subject with a molecule or pool of molecules directed to the BRAF oncogene, culturing the sample in the presence of the agent, and determining whether BRAF oncogene expression by the cells is decreased, and/or whether the cells return to a less transformed phenotype, exhibit decreased cell proliferation, and/or increased contact inhibition. Such changes are indicative that the subject is suffering from rheumatoid arthritis associated with the BRAF oncogene.
The problem addressed is that synovial fibroblasts destroy articular cartilage and bone in rheumatoid arthritis, yet the mechanism of fibroblast transformation responsible for this remains elusive. Although rheumatoid synovial fibroblasts show evidence of transformation such as excessive proliferation, loss of contact inhibition, and increased migration, oncogenes responsible for this transformation have not been identified. The invention addresses this knowledge gap by examining BRAF mutations and aberrant splice variants found in rheumatoid synovial fibroblasts and establishes a new target for therapeutic intervention.
Claims Coverage
The claims include one independent claim focusing on a method to identify molecules binding or blocking BRAF protein in synovial fibroblasts associated with rheumatoid arthritis.
Method to identify molecules binding or blocking BRAF protein in synovial fibroblasts
The method comprises: (a) contacting a molecule of interest with BRAF protein in synovial fibroblasts associated with a BRAF oncogene; and (b) determining whether the molecule of interest alters BRAF protein activity in the fibroblast, where alteration indicates binding or blocking of the BRAF protein.
The claim specifically covers a screening method to identify agents that bind or block BRAF protein activity in rheumatoid arthritis synovial fibroblasts, thereby enabling identification of potential therapeutic molecules.
Stated Advantages
Identification of BRAF mutations and aberrant splice variants establishes a new therapeutic target in rheumatoid arthritis.
BRAF-specific siRNA inhibits proliferation of mutant fibroblasts, indicating a pathway for effective treatment.
Methods enable diagnosing rheumatoid arthritis associated with BRAF oncogene by assessing transformation reversal in fibroblasts.
Documented Applications
Diagnosis of rheumatoid arthritis associated with BRAF oncogene by detecting decreased BRAF expression, reduced cell proliferation, or restored contact inhibition in fibroblasts exposed to BRAF-targeted agents.
Treatment of rheumatoid arthritis via administering agents that bind or inhibit BRAF protein, including siRNA, antisense molecules, or small molecule inhibitors.
Screening and identification of molecules that bind or block BRAF protein activity in synovial fibroblasts for therapeutic use.
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