Methods and Compositions for Treating Phenylketonuria

Patent metadata

Field	Value
Publication number	US-2021121537-A1
Application number	US-202017064332-A
Country	US
Kind code	A1
Filing date	Oct 6, 2020
Priority date	Jul 17, 2015
Publication date	Apr 29, 2021
Grant date	—

Abstract

The present invention provides compositions and methods of treating hyperphenylalaninemia (e.g., phenylketonuria) in a subject in need thereof comprising administering to the subject an effective amount of a phenylalanine dehydrogenase (PheDH) polypeptide. The present invention also provides pharmaceutical formulations comprising PheDH for lowering the phenylalanine concentration in the subject (e.g., in the intestines and/or blood).

First claim

1 - 37 . (canceled)

38 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding a phenylalanine dehydrogenase polypeptide, or a functional fragment thereof, wherein the encoded polypeptide or functional fragment has at least about 80% sequence identity to a wild-type phenylalanine dehydrogenase enzyme or functional fragment thereof from the organism Geobacillus thermoglucosidasius.

39 . The isolated nucleic acid molecule of claim 38 , wherein the nucleotide sequence is a codon-optimized sequence for expression in a host cell

40 . The isolated nucleic acid molecule of claim 38 , wherein the wild-type phenylalanine dehydrogenase enzyme or functional fragment thereof from the organism Geobacillus thermoglucosidasius comprises the amino acid sequence of SEQ ID NO: 1.

41 . The isolated nucleic acid molecule of claim 38 , wherein the encoded polypeptide or functional fragment thereof has at least about 95% sequence identity to the amino acid sequence of SEQ ID NO: 1.

42 . The isolated nucleic acid molecule of claim 38 , wherein the encoded polypeptide or functional fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11.

43 . The isolated nucleic acid molecule of claim 38 , wherein the nucleic acid molecule has been codon-optimized for expression in a bacterial cell, a yeast cell, an insect cell, or a mammalian cell.

44 . The isolated nucleic acid molecule of claim 38 , wherein the nucleic acid molecule has been codon-optimized for expression in Escherichia coli.

45 . The isolated nucleic acid molecule of claim 38 , wherein the nucleotide sequence encoding the phenylalanine dehydrogenase polypeptide or functional fragment thereof comprises the nucleotide sequence of SEQ ID NO: 3.

46 . The isolated nucleic acid molecule of claim 38 , wherein the nucleotide sequence encoding the phenylalanine dehydrogenase polypeptide or functional fragment thereof is operably linked to a promoter sequence.

47 . A plasmid comprising the isolated nucleic acid molecule of claim 38 .

48 . A host cell comprising the isolated nucleic acid molecule of claim 38 .

49 . The host cell of claim 45 , wherein the host cell is Escherichia coli, Bacillus subtilis, Pichia pastoris , or Saccharomyces cerevisiae.

Assignees

• Kobayashi Dione T
• Mcarthur James G
• Childrens Nat Medical Ct

Inventors

• Summar Marshall
• Cabrera-Luque Juan
• Cunningham Gary
• Kobayashi Dione T
• Mcarthur James G

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C12N9/0014

  acting on the CH-NH2 group of donors (1.4) · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K38/44 Primary

  Oxidoreductases (1) · CPC title

• A61K38/51

  Lyases (4) · CPC title