# US 11,110,076 B2 · Methods of treating disorders associated with glycosylation defective proteins

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- Number: US 11,110,076 B2
- Document ID: US11110076B2
- Status: Granted
- Kind: B2
- Application number: 16/793,861
- Filed: 2020-02-18
- Published: 2020-06-11
- Granted: 2021-09-07
- Earliest claimed: 2016-10-07
- Assignees: Case Western Reserve University
- Applicants: Case Western Reserve University
- Inventors: Alagramam N. Kumar; Suhasini Gopal Ramanujam
- Web page: https://patentgrep.com/patent/US11110076B2

## CPC

- A61K 31/357: having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A61P 27/16: Otologicals
- 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

A method of treating a glycosylation-defective protein associated disease or disorder in a subject, the method includes administering to the subject a therapeutically effective amount of a Sarco/ER ATPase (SERCA) inhibitor.

## Claims

### Claim 1

A method of treating a glycosylation-defective protein associated disease or disorder in a subject in need thereof, the method comprising:
administering to the subject a therapeutically effective amount of a Sarco/ER ATPase (SERCA) inhibitor, wherein the SERCA inhibitor induces unconventional secretory pathway transport of aggregated glycosylation-defective protein from endoplasmic reticulum of cells of the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the SERCA inhibitor reduces endoplasmic reticulum luminal calcium levels.

### Claim 3 (depends on 1)

The method of claim 1, wherein the SERCA inhibitor induces activation of the GRASP55 cargo dependent unconventional secretory pathway (GCUSP).

### Claim 4 (depends on 1)

The method of claim 1, the SERCA inhibitor selected from the group consisting of Artemisinin, Artesunate (Arts), thapsigargin, mipsagargin, DBHQ (2,5-di-tert-butylhydroquinone), Saikosaponin-d (Ssd), SBF-1, ruthenium red, curcumin, F36, gingerol, paxilline, cyclopiazonic acid, sHA14-1, CXL017, and analogs thereof.

### Claim 5 (depends on 1)

The method of claim 1, the SERCA inhibitor comprising Artesunate (Arts).

### Claim 6 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount is the amount required to increase cytosolic calcium levels and perturb ER in cells of the subject.

### Claim 7 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount is an amount effective to potentiate ER stress and unfolded protein response (UPR) in cells of the subject.

### Claim 8 (depends on 1)

The method of claim 1, the glycosylation-defective protein associated disease or disorder is a human cystic fibrosis transmembrane conductance regulator (CFTR) protein defect related disease or disorder.

### Claim 9 (depends on 7)

The method of claim 7, the hCFTR defect related disease or disorder is a ΔF508CFTR mutation related disease or disorder.

### Claim 10 (depends on 1)

The method of claim 1, the SERCA inhibitor being administered to the subject by at least one of ophthalmic, topical, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, intradermal, transdermal, buccal, oromucosal, oral, or inhalation administration.

### Claim 11

A method of treating cystic fibrosis associated with a ΔF508CFTR mutation of human cystic fibrosis transmembrane conductance regulator (CFTR) protein in a subject in need thereof, the method comprising:
administering to the subject a therapeutically effective amount of a Sarco/ER ATPase (SERCA) inhibitor.

### Claim 12 (depends on 11)

The method of claim 11, wherein the SERCA inhibitor reduces endoplasmic reticulum luminal calcium levels.

### Claim 13 (depends on 11)

The method of claim 11, wherein the SERCA inhibitor induces activation of the GRASP55 cargo dependent unconventional secretory pathway (GCUSP).

### Claim 14 (depends on 11)

The method of claim 11, the SERCA inhibitor selected from the group consisting of Artemisinin, Artesunate (Arts), thapsigargin, mipsagargin, DBHQ (2,5-di-tert-butylhydroquinone), Saikosaponin-d (Ssd), SBF-1, ruthenium red, curcumin, F36, gingerol, paxilline, cyclopiazonic acid, sHA14-1, CXL017, and analogs thereof.

### Claim 15 (depends on 14)

The method of claim 14, the SERCA inhibitor comprising Artesunate (Arts).

### Claim 16 (depends on 11)

The method of claim 11, wherein the therapeutically effective amount is the amount required to increase cytosolic calcium levels and perturb ER in cells of the subject.

### Claim 17 (depends on 11)

The method of claim 11, wherein the therapeutically effective amount is an amount effective to potentiate ER stress and unfolded protein response (UPR) in cells of the subject.

### Claim 18 (depends on 11)

The method of claim 11, the SERCA inhibitor being administered to the subject by at least one of ophthalmic, topical, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, intradermal, transdermal, buccal, oromucosal, oral, or inhalation administration.