# US 11,992,495 B2 · Enhancing GABA's ability to modulate immune responses

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- Number: US 11,992,495 B2
- Document ID: US11992495B2
- Status: Granted
- Kind: B2
- Application number: 16/625,181
- Filed: 2018-06-20
- Published: 2020-05-07
- Granted: 2024-05-28
- Earliest claimed: 2017-06-23
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Daniel Kaufman; Jide Tian
- Web page: https://patentgrep.com/patent/US11992495B2

## CPC

- A61K 31/5517: condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 9/20: Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)}
- A61K 31/5513: 1,4-Benzodiazepines, e.g. diazepam {or clozapine}
- A61K 31/57: substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/02: Immunomodulators
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Embodiments methods of reducing an inflammatory immune response (e.g., inhibiting a Th1 response) and/or promoting a regulatory immune response (e.g., enhancing Treg(s)) in a mammal are provided where the method methods involve administering to the mammal a GABAA receptor positive allosteric modulator (PAM) in an amount sufficient to reduce an inflammatory immune response and/or to promote a regulatory immune response said mammal. In certain embodiments the PAM is administered in conjunction with a GABA receptor activating ligand (e.g., GABA).

## Claims

### Claim 1

A method of reducing an inflammatory immune response and/or promoting a regulatory immune response in a mammal, said method comprising administering to said mammal the GABAA receptor positive allosteric modulator (PAM) alprazolam and the GABA receptor activating ligand GABA, wherein the dose of GABA would be sufficient to achieve a reduction of an inflammatory immune response and/or promotion of a regulatory immune response when used alone, and the dose of alprazolam is sufficient to increase the reduction of an inflammatory immune response and/or promotion of a regulatory immune response, and wherein the combination of said alprazolam and GABA is more effective to reduce an inflammatory immune response and/or to promote a regulatory immune response in said mammal than when either agent is administered alone.

### Claim 2 (depends on 1)

The method of claim 1, wherein said reduction in an inflammatory immune response or promotion of a regulatory immune response comprises a downregulation of one or more inflammatory cytokines or chemokines selected from the group consisting of IL-1, IL-12, IL-6, IL-17, tumor necrosis factor (TNF), interferon gamma (IFN-γ), granulocyte-macrophage colony stimulating factor (GMCSF), and IL-23.

### Claim 3 (depends on 1)

The method according to claim 1, wherein said reduction in an inflammatory immune response or promotion of a regulatory immune response comprises a reduction of one or more inflammation-related T-cell types.

### Claim 4 (depends on 1)

The method according to claim 1, wherein said mammal is a human.

### Claim 5 (depends on 4)

The method of claim 4, wherein said mammal is a human diagnosed with type I diabetes.

### Claim 6 (depends on 4)

The method of claim 4, wherein said mammal is diagnosed as pre-diabetic.

### Claim 7 (depends on 1)

The method according to claim 1, wherein said mammal is a non-human mammal.

### Claim 8 (depends on 1)

The method according to claim 1, wherein said GABA receptor activating ligand and said PAM act synergistically to reduce an inflammatory immune response and/or to promote a regulatory immune response.

### Claim 9 (depends on 1)

The method of claim 1, wherein said alprazolam is administered at a dosage less than that used to treat used to treat an anxiety disorder, a panic disorder, and/or anxiety caused by depression.

### Claim 10 (depends on 1)

The method of claim 1, wherein said alprazolam is administered as an immediate release tablet less than 1.5 mg orally per day or less than 1.0 mg orally per day, or less than 0.5 mg orally per day, or as an extended release tablet less than 0.5 mg orally per day, or less than about 0.4 mg orally per day or less than about 3 mg orally per day.

### Claim 11 (depends on 1)

The method according to claim 1, wherein said method is used to treat an inflammatory disease.

### Claim 12 (depends on 11)

The method of claim 11, wherein said method is used to treat a disease selected from the group consisting of type I diabetes (T1D), rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, and multiple sclerosis.

### Claim 13 (depends on 1)

The method according to claim 1, wherein said method is used to prevent or lessen graft rejection in a subject receiving a tissue graft.

### Claim 14 (depends on 1)

The method according to claim 1 wherein said method is used to reduce an allergic response.

### Claim 15 (depends on 1)

The method according to claim 1, wherein alprazolam is administered at a dose below that used for CNS indications.