# US 10,864,285 B2 · Methods for the diagnosis and treatment of Sjögren's syndrome

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- Number: US 10,864,285 B2
- Document ID: US10864285B2
- Status: Granted
- Kind: B2
- Application number: 15/798,969
- Filed: 2017-10-31
- Published: 2018-03-08
- Granted: 2020-12-15
- Earliest claimed: 2012-09-25
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Applicants: The U.S.A., as represented by the Secretary, Department of Health and Human Services
- Inventors: John A. Chiorini; Hongen Yin
- Web page: https://patentgrep.com/patent/US10864285B2

## CPC

- A61K 49/0004: {Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions}
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61K 38/179: {for growth factors; for growth regulators}
- C07K 16/22: against growth factors {; against growth regulators}
- C12N 15/1136: {against growth factors, growth regulators, cytokines, lymphokines or hormones}
- C12N 15/115: Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith {; Nucleic acids binding to non-nucleic acids, e.g. aptamers}
- C12Q 1/6883: for diseases caused by alterations of genetic material
- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- G01N 33/6893: {related to diseases not provided for elsewhere}
- G01N 33/74: involving hormones {or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors}
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C12N 2320/30: Special therapeutic applications
- G01N 2333/4704: Inhibitors; Supressors
- G01N 2333/51: Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
- G01N 2800/101: Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## 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.

## Claims

### Claim 1

A method of diagnosing and treating Sjögren's syndrome in a subject, comprising:
performing electrophysiologic tissue measurements of electrical potential or tissue impedance in a diagnostic circuit between a detection electrode in a salivary gland of the subject and a reference electrode in adjacent tissue;
diagnosing the subject as having Sjögren's syndrome (i) detecting an increase in electrical potential or tissue impedance of the subject relative to a healthy control subject, and (ii) detecting the presence of autoantibodies to Ro (SSA) antigen in a serum sample obtained from the subject; and
administering to the subject a therapeutically effective amount of an agent that promotes salivary production, a corticosteroid, an immunosuppressive drug, or a non-steroidal anti-inflammatory drug, thereby treating Sjögren's syndrome in the subject.

### Claim 2 (depends on 1)

The method of claim 1, comprising selecting a subject with symptoms of dry eye or dry mouth prior to performing electrophysiologic tissue measurements.

### Claim 3 (depends on 1)

The method of claim 1, wherein the increase in electrical potential or tissue impedance is at least 10% relative to the healthy control subject.

### Claim 4 (depends on 1)

The method of claim 1, wherein the increase in electrical potential or tissue impedance is at least 30% relative to the healthy control subject.

### Claim 5 (depends on 1)

The method of claim 1, wherein the increase in electrical potential or tissue impedance is at least 50% relative to the healthy control subject.

### Claim 6 (depends on 1)

The method of claim 1, wherein the salivary gland is the submandibular gland or the parotid gland.

### Claim 7 (depends on 1)

The method of claim 1, wherein electrical potential is measured using a device comprising a voltmeter, a detection electrode and a reference electrode, wherein the detection electrode comprises a cannula having a tip of a diameter suitable for insertion into the duct of a salivary gland, the reference electrode is suitable for attachment to tissue external and adjacent to the duct of the salivary gland, and the detection and reference electrodes establish a conductive pathway for an electrical current and determination of a voltage difference between the detection and reference electrodes.

### Claim 8 (depends on 7)

The method of claim 7, wherein the reference electrode is placed on oral mucosa less than 5 cm from the detection electrode.

### Claim 9 (depends on 8)

The method of claim 8, wherein the reference and detection electrodes are placed no more than 3 cm apart.

### Claim 10 (depends on 7)

The method of claim 7, wherein the conductive pathway comprises in part a liquid pathway.

### Claim 11 (depends on 10)

The method of claim 10, wherein the conductive pathway further comprises a cannula suitable for insertion into the salivary gland and a liquid-filled syringe that provides a source of liquid for injection into the cannula, whereby the liquid at least partially establishes electrical current between the salivary gland and detection electrode.

### Claim 12 (depends on 1)

The method of claim 1, further comprising performing sequential electrophysiologic tissue measurements to assess changes in severity of Sjögren's syndrome or response to administering the agent that promotes salivary production, the corticosteroid, the immunosuppressive drug, or the non-steroidal anti-inflammatory drug.

### Claim 13 (depends on 1)

The method of claim 1, wherein the method comprises administering the corticosteroid.

### Claim 14 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 15 (depends on 1)

The method of claim 1, wherein the subject is a mouse.

### Claim 16 (depends on 1)

The method of claim 1, wherein the agent that promotes salivary production is pilocarpine or cevimeline.

### Claim 17 (depends on 13)

The method of claim 13, wherein the corticosteroid is cortisol or prednisone.