# US 11,077,105 B2 · Therapy for mitochondrial fatty acid beta-oxidation and transport disorders

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- Number: US 11,077,105 B2
- Document ID: US11077105B2
- Status: Granted
- Kind: B2
- Application number: 16/345,757
- Filed: 2017-11-15
- Published: 2019-09-26
- Granted: 2021-08-03
- Earliest claimed: 2016-11-15
- Assignees: University of Pittsburgh—Of the Commonwealth System of Higher Education
- Applicants: University of Pittsburgh—Of the Commonwealth System of Higher Education
- Inventors: Al-Walid A. Mohsen; Gerard Vockley
- Web page: https://patentgrep.com/patent/US11077105B2

## CPC

- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/426: 1,3-Thiazoles
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61K 38/45: Transferases (2)
- 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

Methods of treating mitochondrial fatty acid b-oxidation and/or transport disorders arising from mutant proteins in the mitochondrial fatty acid β-oxidation and transport metabolic pathways in patients are provided. The methods modulate the mitochondrial fatty acid β-oxidation pathway at the last step so that the product of the mutant protein accumulates and stabilizes the mutant protein and/or the substrate(s)/product(s) of the down stream reactions accumulate and possibly bind to allosteric sites on the mutant protein to stabilize it. Trimetazidine pharmacodynamics function as such in the β-oxidation pathway. Further, a synergistic effect is observed where trimetazidine and PPARδ agonist combination enhanced enzyme activity and presence significantly more than either alone.

## Claims

### Claim 1

A method of increasing activity of an enzyme of a β-oxidation pathway or fatty acid mitochondrial transporter protein/enzyme, the enzyme of the β-oxidation pathway or fatty acid mitochondrial transporter protein/enzyme having a missense mutation resulting in loss of its activity or stability, in a patient in need thereof, comprising administering to the patient an effective amount of an inhibitor of activity of an enzyme of the β-oxidation pathway downstream in the β-oxidation pathway of the enzyme of the β-oxidation pathway or fatty acid mitochondrial transporter protein/enzyme having the mis sense mutation, thereby increasing activity of the enzyme of the β-oxidation pathway or fatty acid mitochondrial transporter protein/enzyme having the missense mutation, wherein the product, optionally a reverse reaction substrate, of the enzyme of the β-oxidation pathway or fatty acid mitochondrial transporter protein/enzyme having the missense mutation binds and stabilizes the enzyme of the β-oxidation pathway or fatty acid mitochondrial transporter protein/enzyme,
wherein the enzyme of the β-oxidation pathway or fatty acid mitochondrial transporter protein/enzyme is selected from the group consisting of very long chain acyl-CoA dehydrogenase (VLCAD), mitochondrial trifunctional protein (TFP), long-chain 3-ketoacyl-CoA thiolase (LCKAT), and mitochondrial membrane fatty acid transport protein.

### Claim 2 (depends on 1)

The method of claim 1, wherein the missense mutation does not result in a complete loss of enzyme activity.

### Claim 3 (depends on 1)

The method of claim 1, wherein the missense mutation is L540P, V174M, E609K, or any other VLCAD or VLCAD isoforms, harboring any destabilizing missense mutation(s).

### Claim 4 (depends on 1)

The method of claim 1, wherein the TFP is the α-subunit or the β-subunit encoded by HADHA or HADHB genes, respectively.

### Claim 5 (depends on 4)

The method of claim 4, wherein the mis sense mutation is E510Q of HADHA, or any destabilizing missense mutations.

### Claim 6 (depends on 4)

The method of claim 4, wherein the missense mutation is R247C of HADHB, or any destabilizing mis sense mutations.

### Claim 7 (depends on 1)

The method of claim 1, wherein the enzyme of the β-oxidation pathway downstream in the β-oxidation pathway to the enzyme having the missense mutation is long-chain 3-ketoacyl-CoA thiolase (LCKAT).

### Claim 8 (depends on 1)

The method of claim 1, wherein activity of the enzyme of the β-oxidation pathway downstream in the β-oxidation pathway to the enzyme having the mis sense mutation is inhibited by trimetazidine or a derivative thereof, or a pharmaceutically-acceptable salt or ester thereof.

### Claim 9 (depends on 1)

The method of claim 1, wherein the mitochondrial membrane fatty acid transport protein is carnitine palmitoyltransferase I (CPT I) or carnitine palmitoyltransferase 2 (CPT II).

### Claim 10 (depends on 1)

The method of claim 1, further comprising administering to the patient an amount of a Peroxisome Proliferator-Activated Receptor delta (PPARδ) agonist effective to increase activity of the enzyme of the β-oxidation pathway or fatty acid mitochondrial transport protein/enzyme having the mis sense mutation in the patient.

### Claim 11 (depends on 10)

The method of claim 10, wherein the PPARδ agonist is chosen from GW501516, GW0742, or any PPARδ agonist that enhances production activity of the enzyme of the β-oxidation pathway or fatty acid mitochondrial transport protein/enzyme having the missense mutation.