Methods for the diagnosis and treatment of Sjögren's syndrome
Inventors
Chiorini, John A. • Yin, Hongen
Assignees
US Department of Health and Human Services
Publication Number
US-10864285-B2
Publication Date
2020-12-15
Expiration Date
2033-09-25
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Abstract
The finding that patients with Sjögren's syndrome exhibit a statistically significant increase in expression of BMP6 in the salivary gland relative to healthy control subjects is described. Also described is the finding that overexpression of BMP6 in the salivary glands of mice results in an increase in electrical potential across the salivary gland. Thus, methods of diagnosing a subject as having Sjögren's syndrome, or at risk for developing Sjögren's syndrome, by measuring the level of BMP6 expression in a salivary gland of a subject, measuring electrical potential in a salivary gland of a subject, or both, are disclosed. Also described are methods of treating a subject with Sjögren's syndrome by administering an agent that inhibits expression of BMP6 expression or activity. Further disclosed is the use of XIST and MECP2 as diagnostic and therapeutic targets for male Sjögren's syndrome patients.
Core Innovation
The invention discloses that patients with Sjögren's syndrome exhibit a statistically significant increase in expression of bone morphogenetic protein 6 (BMP6) in the salivary gland compared to healthy control subjects. It also describes that overexpression of BMP6 in the salivary glands of mice results in an increase in electrical potential across the salivary gland.
Methods for diagnosing Sjögren's syndrome include detecting an increase in BMP6 expression in a biological sample (such as a salivary gland biopsy), measuring electrical potential or impedance in a salivary gland, or both. A diagnostically significant increase in BMP6 expression or electrical potential compared to control values diagnoses the subject as having or at risk for developing Sjögren's syndrome.
For treatment, methods include administering to a subject with Sjögren's syndrome an agent that inhibits expression or activity of BMP6 or inhibits BMP signaling. These agents include antibodies, nucleic acid molecules such as antisense oligonucleotides or chimeric U7 snRNAs targeting BMP6, soluble binding molecules, RNA aptamers, or small molecule inhibitors such as dorsomorphin. Further, the use of XIST and MECP2 as diagnostic and therapeutic targets is disclosed specifically for male patients with Sjögren's syndrome, wherein males abnormally express XIST and down-regulate MECP2.
Claims Coverage
The claims primarily cover a method combining electrophysiologic tissue measurements with autoantibody detection to diagnose Sjögren's syndrome, followed by administering therapeutic agents.
Diagnosing Sjögren's syndrome by electrophysiologic tissue measurements combined with autoantibody detection
Performing electrophysiologic tissue measurements of electrical potential or tissue impedance using a circuit between a detection electrode in a salivary gland and a reference electrode in adjacent tissue to detect an increase relative to healthy controls, and simultaneously detecting autoantibodies to Ro (SSA) antigen in serum to diagnose Sjögren's syndrome.
Treating diagnosed subjects with therapeutic agents
Administering to the diagnosed subject a therapeutically effective amount of an agent that promotes salivary production, a corticosteroid, an immunosuppressive drug, or a non-steroidal anti-inflammatory drug to treat Sjögren's syndrome.
Use of specific device for measuring electrical potential
Measuring electrical potential using a device comprising a voltmeter, a detection electrode with a cannula suitable for insertion into a salivary gland duct, and a reference electrode attached to tissue adjacent to the duct, establishing a conductive pathway for electrical measurement.
Electrode placement and conductive pathway details
Positioning the reference electrode on oral mucosa less than 5 cm (preferably no more than 3 cm) from the detection electrode, and forming at least part of the conductive pathway through a liquid pathway, including a liquid-filled syringe connected to the cannula inserted in the salivary gland.
Sequential electrophysiologic measurements to monitor disease
Performing sequential electrophysiologic tissue measurements to assess changes in severity of Sjögren's syndrome or response to administered therapy.
The claims focus on a diagnostic method combining electrophysiologic measurements with autoantibody detection for Sjögren's syndrome and therapeutic treatment with established agents. The claims also include details of the diagnostic device and measurement procedures, as well as monitoring disease progression by sequential measurements.
Stated Advantages
Provides an objective, reproducible standard for diagnosing Sjögren's syndrome and assessing disease course or response to therapy without relying exclusively on subjective criteria.
Enables detection of Sjögren's syndrome through measurable increases in BMP6 expression and electrical potential changes in the salivary gland.
Identifies new diagnostic markers and therapeutic targets, including BMP6, XIST, and MECP2, particularly addressing male Sjögren's syndrome patients.
Allows separation of immune infiltration from loss of salivary gland function, aiding better understanding of disease mechanisms.
Documented Applications
Diagnosis of Sjögren's syndrome by detecting increased BMP6 expression in salivary gland tissues or measuring increased electrical potential or tissue impedance in the salivary gland.
Treatment of Sjögren's syndrome by administering agents that inhibit BMP6 expression or activity, BMP signaling inhibitors, or agents targeting XIST and MECP2 expression in male patients.
Using electrophysiologic measurement devices to objectively diagnose Sjögren's syndrome and monitor disease progression or response to therapy.
Diagnostic and therapeutic applications of detecting and modulating XIST and MECP2 expression specifically in male Sjögren's syndrome patients.
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