# US 11,077,175 B2 · Compositions and methods for treatment of homocystinuria

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- Number: US 11,077,175 B2
- Document ID: US11077175B2
- Status: Granted
- Kind: B2
- Application number: 16/824,931
- Filed: 2020-03-20
- Published: 2020-09-03
- Granted: 2021-08-03
- Earliest claimed: 2020-03-20
- Assignees: The Regents of the University of Colorado, a body corporate
- Applicants: The Regents of the University of Colorado, A Body Corporate
- Inventors: Jan P. Kraus; Tomas Majtan; Erez Bublil
- Web page: https://patentgrep.com/patent/US11077175B2

## CPC

- A61K 38/51: Lyases (4)
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/205: Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
- A61K 31/385: having two or more sulfur atoms in the same ring
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 17/14: for baldness or alopecia
- A61P 19/10: for osteoporosis
- A61P 27/02: Ophthalmic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 9/88: Lyases (4.)
- C12N 9/96: Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
- C12Y 402/01022: Cystathionine beta-synthase (4.2.1.22)
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- 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

Provided are compositions and methods for enzyme replacement therapy using modified human cystathionine beta synthase (CBS) in the treatment of homocystinuria and related diseases and disorders.

## Claims

### Claim 1

A method of treating one or more symptom of liver disease in a subject, the method comprising administering to the subject a composition comprising an isolated human C-terminal truncated cystathionine beta synthase (htCBS) mutant polypeptide having a C15S mutation, wherein:
the isolated htCBS mutant polypeptide has been PEGylated;
the isolated htCBS mutant polypeptide is administered in a dose between about 0.01 and about 10 mg/kg; and
wherein the subject has homocystinuria or a pathogenic CBS gene mutation.

### Claim 2 (depends on 1)

The method of claim 1, wherein the one or more symptom of liver disease comprises:
liver parenchyma damage in the subject;
hepatic microvesicular steatosis in the subject;
hepatic macrovesicular steatosis in the subject;
focal hepatocellular necroses in the subject; or
resorptive inflammatory response in the subject.

### Claim 3 (depends on 1)

The method of claim 1, wherein the htCBS mutant polypeptide has the amino acid sequence of SEQ ID NO: 13.

### Claim 4 (depends on 3)

The method of claim 3, wherein the htCBS mutant polypeptide lacks the N-terminal first methionine residue.

### Claim 5 (depends on 1)

The method of claim 1, wherein the administering comprises long-term treatment comprising intravenous administration 1 time, 2 times, or 3 times per week for at least 5 weeks.

### Claim 6 (depends on 1)

The method of claim 1, wherein the administering comprises continuous long-term administration.

### Claim 7 (depends on 1)

The method of claim 1, further comprising restricting the subject to a methionine-restricted diet.

### Claim 8

A method of treating one or more skeletal symptoms in a subject, the method comprising administering to the subject a composition comprising an isolated human C-terminal truncated cystathionine beta synthase (htCBS) mutant polypeptide having a C15S mutation, wherein:
the isolated htCBS mutant polypeptide has been PEGylated;
the isolated htCBS mutant polypeptide is administered in a dose between about 0.01 and about 10 mg/kg; and
wherein the subject has homocystinuria or a pathogenic CBS gene mutation.

### Claim 9 (depends on 8)

The method of claim 8, wherein the one or more skeletal symptoms comprise:
reduced bone mineralization;
reduced bone density;
marfanoid habitus;
osteoporosis;
scoliosis;
fine hair; or
brittle skin.

### Claim 10 (depends on 8)

The method of claim 8, wherein the htCBS mutant polypeptide has the amino acid sequence of SEQ ID NO: 13.

### Claim 11 (depends on 10)

The method of claim 10, wherein the htCBS mutant polypeptide lacks the N-terminal first methionine residue.

### Claim 12 (depends on 8)

The method of claim 8, wherein the administering comprises long-term treatment comprising intravenous administration 1 time, 2 times, or 3 times per week for at least 5 weeks.

### Claim 13 (depends on 8)

The method of claim 8, wherein the administering comprises continuous long-term administration.

### Claim 14 (depends on 8)

The method of claim 8, further comprising restricting the subject to a methionine-restricted diet.

### Claim 15

A method of treating one or more ocular symptoms in a subject, the method comprising administering to the subject a composition comprising an isolated human C-terminal truncated cystathionine beta synthase (htCBS) mutant polypeptide having a C15S mutation, wherein:
the isolated htCBS mutant polypeptide has been PEGylated;
the isolated htCBS mutant polypeptide is administered in a dose between about 0.01 and about 10 mg/kg; and
wherein the subject has homocystinuria or a pathogenic CBS gene mutation.

### Claim 16 (depends on 15)

The method of claim 15, wherein the one or more ocular symptoms comprise:
progressive myopia;
lens dislocation (ectopia lentis); or
reduced density of zonular fibers.

### Claim 17 (depends on 15)

The method of claim 15, wherein the htCBS mutant polypeptide has the amino acid sequence of SEQ ID NO: 13.

### Claim 18 (depends on 17)

The method of claim 17, wherein the htCBS mutant polypeptide lacks the N-terminal first methionine residue.

### Claim 19 (depends on 15)

The method of claim 15, wherein the administering comprises long-term treatment comprising intravenous administration 1 time, 2 times, or 3 times per week for at least 5 weeks.

### Claim 20 (depends on 15)

The method of claim 15, wherein the administering comprises continuous long-term administration.

### Claim 21 (depends on 15)

The method of claim 15, further comprising restricting the subject to a methionine-restricted diet.

### Claim 22

A method of increasing plasma lanthionine in a subject, the method comprising administering to the subject a composition comprising an isolated human C-terminal truncated cystathionine beta synthase (htCBS) mutant polypeptide having a C15S mutation, wherein:
the isolated htCBS mutant polypeptide has been PEGylated; and
the isolated htCBS mutant polypeptide is administered in a dose between about 0.01 and about 10 mg/kg.

### Claim 23

A method of increasing cystathionine and/or cysteine in a tissue of a subject, said method comprising administering to the subject a composition comprising an isolated human C-terminal truncated cystathionine beta synthase (htCBS) mutant polypeptide having a C15S mutation, wherein said isolated htCBS mutant polypeptide has been PEGylated, and is administered in a dose between about 0.01 and about 10 mg/kg, wherein the tissue is liver, kidney, or brain.

### Claim 24

A method of decreasing homocysteine, methionine, and/or S-adenosyl homocysteine in a tissue of a subject, said method comprising administering to the subject a composition comprising an isolated human C-terminal truncated cystathionine beta synthase (htCBS) mutant polypeptide having a C15S mutation, wherein said isolated htCBS mutant polypeptide has been PEGylated, and is administered in a dose between 0.01 and 10 mg/kg, wherein the tissue is liver, kidney, or brain.