Modulation of PTPRA to treat arthritis
Inventors
Bottini, Nunzio • Firestein, Gary • Stanford, Stephanie
Assignees
La Jolla Institute for Allergy and Immunology • University of California San Diego UCSD
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Publication Number
US-10604585-B2
Publication Date
2020-03-31
Expiration Date
Abstract
Presented is a method for treating inflammation and autoimmune diseases through the use of a phosphatase rheumatoid arthritis (PT-PRA) antagonist.
Core Innovation
The invention relates to inhibiting receptor-type tyrosine-protein phosphatase alpha (PTPRA), also referred to as RPTPα, protein activity in a cell. In particular, the cell is a fibroblast-like synoviocyte (FLS), and the approach is based on contacting the cell with a PTPRA antagonist to inhibit PTPRA protein activity in the cell.
The disclosed rationale links PTPRA (RPTPα) to SRC and downstream signaling, including FAK and JNK pathways. The patent content further associates TNF and IL-1β-driven pro-inflammatory phenotypes and PDGF-driven pro-invasive/aggressive phenotypes in fibroblast-like synoviocytes with PTPRA-regulated signaling.
A treatment concept is described through use of a PTPRA antagonist that is an anti-PTPRA inhibitory nucleic acid. Supporting material in the provided content indicates that PTPRA targeting can be studied by PTPRA knockdown, with measurements of cytokine/chemokine and MMP expression, changes in FLS invasiveness/migration/survival, and signaling readouts including SRC Tyr527, FAK Tyr397, JNK, p38, AKT, and NF-κB.
Claims Coverage
The provided content includes one independent claim and related refinements. It covers inhibiting PTPRA protein activity in a fibroblast-like synoviocyte by contacting the cell with an anti-PTPRA inhibitory nucleic acid, with further claim features directed to sequence identity, morpholino format, antisense and phosphoramidate characteristics, and conjugation to a cell permeable moiety.
Inhibiting PTPRA protein activity in fibroblast-like synoviocytes with an anti-PTPRA inhibitory nucleic acid
A method of inhibiting receptor-type tyrosine-protein phosphatase alpha (PTPRA) protein activity in a cell by contacting a fibroblast-like synoviocyte with an effective amount of an anti-PTPRA inhibitory nucleic acid, thereby inhibiting PTPRA protein activity in said cell.
Anti-PTPRA inhibitory nucleic acid with sequence identity to SEQ ID NOs
The method includes an anti-PTPRA inhibitory nucleic acid having at least 90% sequence identity to at least 10 contiguous nucleotides of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3, or a complementary sequence thereof.
Morpholino anti-PTPRA inhibitory nucleic acid
The method uses an anti-PTPRA inhibitory nucleic acid that is a morpholino nucleic acid.
Single-stranded antisense morpholino
The method uses a morpholino nucleic acid that is a single-stranded antisense nucleic acid.
Phosphoramidate morpholino
The method uses a morpholino nucleic acid that is a phosphoramidate morpholino nucleic acid.
Conjugation of the morpholino to a cell permeable moiety
The method further characterizes that the morpholino nucleic acid is conjugated to a cell permeable moiety.
The inventive coverage centers on inhibition of PTPRA protein activity in fibroblast-like synoviocytes using an anti-PTPRA inhibitory nucleic acid, with defined sequence identity and morpholino-related limitations.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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