Compositions and methods for treatment of homocystinuria

• US 10,729,753 B2
• Filed: 01/09/2019
• Issued: 08/04/2020
• Est. Priority Date: 01/29/2013
• Status: Active Grant

• Current Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Original Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Inventors: Kraus, Jan P., Majtan, Tomas, Bublil, Erez
• Primary Examiner(s): Raghu, Ganapathirama
• Application Number:
  US16/243,295
• Publication Number:
  US 20190125845A1
• Time in Patent Office: 573 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: 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
• CPC Class Codes: A61K 31/205 Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• CPC Class Codes: A61K 31/385 having two or more sulfur atoms in the same ring
• CPC Class Codes: A61K 38/51 Lyases (4)
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: 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
• CPC Class Codes: C12N 9/88 Lyases (4.)
• CPC Class Codes: C12N 9/96 Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
• CPC Class Codes: C12Y 402/01022 Cystathionine beta-synthase (4.2.1.22)

Abstract

Provided herein are improved 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

1. A method of treating a subject having a condition associated with cystathionine β

-synthase deficiency due to a pyridoxine-responsive mutation, the method comprising;

administering to the subject an isolated human truncated cystathionine β

-synthase (htCBS) mutant polypeptide having a C15S mutation compared to SEQ ID NO;

2, wherein the isolated htCBS mutant polypeptide is PEGylated and the C-terminal regulatory region is truncated.

2. The method of claim 1, wherein the isolated htCBS mutant polypeptide is co-administered with betaine.

3. The method of claim 1, wherein betaine is administered prior to the isolated htCBS mutant polypeptide.

4. The method of claim 1, wherein the htCBS mutant polypeptide forms a dimer.

5. The method of claim 1, wherein the htCBS mutant polypeptide does not form a tetramer.

6. The method of claim 1, wherein treating comprises mitigating or reducing pathological events of the condition associated with cystathionine β

-synthase deficiency due to a pyridoxine-responsive mutation in the subject.

7. The method of claim 1, wherein the isolated htCBS is PEGylated with a low molecular weight linear PEG.

8. The method of claim 1, wherein the isolated htCBS is PEGylated with a high molecular weight four arm branched PEG.

9. The method of claim 1, wherein the isolated htCBS is PEGylated with a 20 kDa NHS ester-activated PEG.

10. The method of claim 1, wherein the subject is a partial responder to vitamin B6.

11. The method of claim 1, further comprising administering vitamin B6.

12. A method of treating a disease, disorder, or condition selected from:

mental retardation, a psychiatric disturbance, a central nervous system problem, a cardiovascular disease, and a connective tissue disorder, the method comprising;

administering to the subject an isolated human truncated cystathionine β

-synthase (htCBS) mutant polypeptide having a C15S mutation compared to SEQ ID NO;

2, wherein the isolated htCBS mutant polypeptide is PEGylated and the C-terminal regulatory region is truncated.

13. The method of claim 12, further comprising co-administering betaine with the htCBS mutant polypeptide.

14. The method of claim 12, wherein betaine is administered prior to the isolated htCBS mutant polypeptide.

15. The method of claim 12, wherein the htCBS mutant polypeptide forms a dimer.

16. The method of claim 12, wherein the htCBS mutant polypeptide does not form a tetramer.

17. The method of claim 12, wherein the isolated htCBS is PEGylated with a low molecular weight linear PEG.

18. The method of claim 12, wherein the isolated htCBS is PEGylated with a high molecular weight four arm branched PEG.

19. The method of claim 12, wherein the isolated htCBS is PEGylated with a 20 kDa NHS ester-activated PEG.

20. The method of claim 12, further comprising administering vitamin B6.

21. The method of claim 12, wherein the central nervous system problem is seizures.

22. The method of claim 12, wherein the connective tissue disorder is selected from the group consisting of:

progressive myopia, lens dislocation, ectopia lentis, marfanoid habitus, osteoporosis, scoliosis, fine fair hair, and brittle and thin skin.

23. The method of claim 12, wherein the cardiovascular disease is a predisposition to thromboembolic complications.