# US 2014/0155468 A1 · Methods and compositions for regulation of metabolic disorders

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2014/0155468 A1
- Document ID: US20140155468A1
- Status: Published application
- Kind: A1
- Application number: 14/096,788
- Filed: 2013-12-04
- Published: 2014-06-05
- Earliest claimed: 2012-12-05
- Assignees: Sangamo BioScience, Inc.; The Children's Hospital of Philadelphia
- Applicants: The Children's Hospital of Philadelphia; Sangamo BioSciences, Inc.
- Inventors: Philip D. Gregory; Katherine A. High
- Web page: https://patentgrep.com/patent/US20140155468A1

## CPC

- A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/12: of the kidneys
- C12N 5/10: Cells modified by introduction of foreign genetic material
- A61K 2035/124: {the cells being hematopoietic, bone marrow derived or blood cells}
- 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)

## Abstract

Cells and methods of using these cells for expressing a transgene expressing a protein that is aberrantly expressed in a metabolic disorders from a safe harbor locus.

## Claims

### Claim 1

A cell comprising an exogenous transgene encoding a protein, wherein the exogenous transgene is integrated site-specifically using a nuclease into an endogenous safe harbor gene and further wherein the protein is a functional version of a protein that is aberrantly expressed in a metabolic disorder selected from the group consisting of methylmalonic acidemia, propionic acidemia, glycogen storage diseases type 1, familial hypercholesterolemia (FH) is a common genetic and metabolic disease, urea cycle disorders, Crigler Najjar Syndrome (CNS), Gilbert syndrome, hepatorenal tyrosinemia, primary hyperoxaluria. transthyretin gene (TTR)-mediated amyloidosis (ATTR), Wilson's disease, phenylketonuria (PKU), and familial lipoprotein lipase deficiency (LPLD).

### Claim 2 (depends on 1)

The cell of claim 1, wherein the cell is selected from the group consisting of a hepatic cell, an induced pluripotent stem cell (iPSC), a hematopoietic stem cell, a hepatic cell, a hepatic stem cell, and a red blood precursor cell.

### Claim 3 (depends on 1)

The cell of claim 1, wherein the endogenous safe harbor gene is selected from the group consisting of CCR5, HPRT, AAVS1, Rosa and albumin.

### Claim 4 (depends on 1)

The cell of claim 1, wherein the transgene encodes a protein selected from the group consisting of MMAA, MMAB, MMACHC, MMADHC (C2orf25), MTRR, LMBRD1, MTR, propionyl-CoA carboxylase (PCCA or PCCB), a glucose-6-phosphate transporter (G6PT) protein or glucose-6-phosphatase (G6Pase), an LDL receptor (LDLR), an ApoB protein, an LDLRAP-1 protein, a PCSK9 protein, a mitochondrial protein such as NAGS (N-acetylglutamate synthetase), CPS1 (carbamoyl phosphate synthetase I), and OTC (ornithine transcarbamylase), ASS (argininosuccinic acid synthetase), ASL (argininosuccinase acid lyase) and/or ARG1 (arginase), and/or a solute carrier family 25 (SLC25A13, an aspartate/glutamate carrier) protein, a UGT1A1 or UDP glucuronsyltransferase polypeptide A1, a fumarylacetoacetate hydrolyase (FAH), an alanine-glyoxylate aminotransferase (AGXT) protein, a glyoxylate reductase/hydroxypyruvate reductase (GRHPR) protein, a transthyretin gene (TTR) protein, an ATP7B protein, a phenylalanine hydroxylase (PAH) protein and a lipoprotein lyase (LPL) protein.

### Claim 5 (depends on 1)

The cell of claim 1, wherein expression of the transgene is driven by an endogenous promoter.

### Claim 6 (depends on 1)

The cell of claim 1, wherein the transgene is operably linked to a promoter sequence that drives expression of the transgene.

### Claim 7 (depends on 1)

A method of generating a genetically modified cell according to claim 1, the method comprising administering a nuclease and a vector encoding the transgene to the cell such that the transgene is integrated into the endogenous safe harbor locus.

### Claim 8 (depends on 7)

A method of increasing expression of a protein that is aberrantly expressed in a subject with a metabolic disorder, the method comprising modifying a cell in the subject according to claim 7.

### Claim 9 (depends on 7)

The method of claim of claim 7 wherein the nuclease is administered to the cell via a vector, an mRNA or as an intact protein.

### Claim 10 (depends on 7)

The method of claim 7, wherein the cell is selected from the group consisting of a hepatic cell, an induced pluripotent stem cell (iPSC), a hematopoietic stem cell, a hepatic cell, a hepatic stem cell, and a red blood precursor cell.

### Claim 11 (depends on 7)

The method of claim 7, wherein the endogenous safe harbor gene is selected from the group consisting of CCR5, HPRT, AAVS1, Rosa and albumin.

### Claim 12 (depends on 7)

The method of claim 7, wherein the protein is selected from the group consisting of MMAA, MMAB, MMACHC, MMADHC (C2orf25), MTRR, LMBRD1, MTR, propionyl-CoA carboxylase (PCCA or PCCB), a glucose-6-phosphate transporter (G6PT) protein or glucose-6-phosphatase (G6Pase), an LDL receptor (LDLR), an ApoB protein, an LDLRAP-1 protein, a PCSK9 protein, a mitochondrial protein such as NAGS (N-acetylglutamate synthetase), CPS1 (carbamoyl phosphate synthetase I), and OTC (ornithine transcarbamylase), ASS (argininosuccinic acid synthetase), ASL (argininosuccinase acid lyase) and/or ARG1 (arginase), and/or a solute carrier family 25 (SLC25A13, an aspartate/glutamate carrier) protein, a UGT1A1 or UDP glucuronsyltransferase polypeptide A1, a fumarylacetoacetate hydrolyase (FAH), an alanine-glyoxylate aminotransferase (AGXT) protein, a glyoxylate reductase/hydroxypyruvate reductase (GRHPR) protein, a transthyretin gene (TTR) protein, an ATP7B protein, a phenylalanine hydroxylase (PAH) protein and a lipoprotein lyase (LPL) protein.