# US 12,758,654 B2 · Methods and compositions for the treatment of fabry disease

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- Number: US 12,758,654 B2
- Document ID: US12758654B2
- Status: Granted
- Kind: B2
- Application number: 17/572,189
- Filed: 2022-01-10
- Published: 2022-09-01
- Granted: 2026-10-13
- Earliest claimed: 2016-10-20
- Assignees: Sangamo Therapeutics, Inc.
- Applicants: Sangamo Therapeutics, Inc.
- Inventors: Marshall W. Huston
- Web page: https://patentgrep.com/patent/US12758654B2

## CPC

- A61K 48/0058: {Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct}
- A61K 38/465: {acting on ester bonds (3.1), e.g. lipases, ribonucleases}
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- C12N 5/067: {Hepatocytes}
- C12N 9/2465: {acting on alpha-galactose-glycoside bonds, e.g. alpha-galactosidase (3.2.1.22)}
- C12N 15/86: Viral vectors
- C12Y 301/00: Hydrolases acting on ester bonds (3.1)
- C12Y 302/01022: Alpha-galactosidase (3.2.1.22)
- C12N 2510/00: Genetically modified cells
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

Nucleases and methods of using these nucleases for inserting a sequence encoding a therapeutic α-Gal A protein such as an enzyme into a cell, thereby providing proteins or cell therapeutics for treatment and/or prevention of Fabry disease.

## Claims

### Claim 1

A pharmaceutical composition comprising an adeno-associated virus (AAV) expression construct, wherein the AAV expression construct comprises an apolipoprotein E (APOE) enhancer operably linked to an alpha 1-antitrypsin (hAAT) promoter, a human hemoglobin beta (HBB)-IGG intron, and a cDNA transgene encoding at least one a galactosidase A (α-Gal A) protein, and a pharmaceutically acceptable carrier or excipient.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the AAV expression construct further comprises a sequence encoding a signal peptide.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the AAV expression construct further comprises a poly A signal sequence.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein the transgene comprises a wild-type α-Gal A sequence or a codon-optimized α-Gal A sequence.

### Claim 5 (depends on 2)

The pharmaceutical composition of claim 2, wherein the signal peptide is an α-Gal A signal peptide.

### Claim 6

An adeno-associated virus (AAV) expression construct, wherein the AAV expression construct comprises an apolipoprotein E (APOE) enhancer operably linked to an alpha 1-antitrypsin (hAAT) promoter, a human hemoglobin beta (HBB)-IGG intron, and a cDNA transgene encoding at least one a galactosidase A (α-Gal A) protein.

### Claim 7 (depends on 6)

The AAV expression construct of claim 6, wherein the AAV expression construct further comprises a sequence encoding a signal peptide.

### Claim 8 (depends on 7)

The AAV expression construct of claim 7, wherein the signal peptide is an α-Gal A signal peptide.

### Claim 9

The AAV expression construct of 6, wherein the AAV expression construct further comprises a poly A signal sequence.

### Claim 10 (depends on 9)

The AAV expression construct of claim 9, wherein the polyA signal sequence is a bovine growth hormone poly A signal sequence.

### Claim 11 (depends on 6)

The AAV expression construct of claim 6, wherein the transgene comprises a wild-type α-Gal A sequence or a codon optimized α-Gal A sequence.

### Claim 12

An adeno-associated virus (AAV) expression construct comprising an apolipoprotein E (APOE) enhancer linked to an alpha 1-antitrypsin (hAAT) promoter, a human hemoglobin beta (HBB)-IGG intron, a sequence encoding an α-Gal A signal peptide, a cDNA transgene encoding at least one alpha-galactosidase A (α-Gal A) protein, and a bovine growth hormone poly A signal sequence.

### Claim 13 (depends on 6)

The AAV expression construct of claim 6, wherein the AAV expression construct is capable of expressing at least one α-Gal A protein from the transgene in a subject in need thereof.

### Claim 14 (depends on 13)

The AAV expression construct of claim 13, wherein the at least one α-Gal A protein expressed from the transgene decreases the amount of glycospingolipids in the subject by at least 2-fold.

### Claim 15 (depends on 3)

The pharmaceutical composition of claim 3, wherein the polyA signal sequence is a bovine growth hormone poly A signal sequence.

### Claim 16 (depends on 11)

The AAV expression construct of claim 11, wherein the transgene comprises a codon optimized α-Gal A sequence.

### Claim 17 (depends on 12)

The AAV expression construct of claim 12, wherein the transgene comprises a codon optimized α-Gal A sequence.

### Claim 18 (depends on 4)

The pharmaceutical composition of claim 4, wherein the transgene comprises a codon-optimized α-Gal A sequence.

### Claim 19 (depends on 1)

The pharmaceutical composition of claim 1, wherein the AAV expression construct is capable of expressing at least one α-Gal A protein from the transgene in a subject in need thereof.

### Claim 20 (depends on 19)

The pharmaceutical composition of claim 19, wherein the at least one α-Gal A protein expressed from the transgene decreases the amount of glycospingolipids in the subject by at least 2-fold.