Methods and compositions for treating phenylketonuria

Patent metadata

Field	Value
Publication number	US-10792339-B2
Application number	US-201615212009-A
Country	US
Kind code	B2
Filing date	Jul 15, 2016
Priority date	Jul 17, 2015
Publication date	Oct 6, 2020
Grant date	Oct 6, 2020

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

What is claimed is:

1. A pharmaceutical formulation comprising a phenylalanine dehydrogenase polypeptide, or a functional fragment thereof, and a pharmaceutically-acceptable carrier, wherein the phenylalanine dehydrogenase polypeptide, or the functional fragment thereof, comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 1, wherein the pharmaceutical formulation is in a solid or semi-solid dosage form, or contained within an artificial membrane.

2. The pharmaceutical formulation of claim 1 , wherein the formulation is in the form of a tablet.

3. The pharmaceutical formulation of claim 1 , wherein the formulation is in the form of a capsule or a liquid.

4. The pharmaceutical formulation of claim 3 , wherein the capsule is coated with a polymer that is resistant to acidic pH, degradation by digestive enzymes, or both.

5. The pharmaceutical formulation of claim 1 , wherein the phenylalanine dehydrogenase polypeptide, or functional fragment thereof, is stable and active in the gastrointestinal tract of the subject.

6. The pharmaceutical formulation of claim 1 , wherein the formulation is a sustained-release formulation.

7. The pharmaceutical formulation of claim 6 , wherein the sustained-release formulation includes NAD + or an NAD + analog.

8. A method of reducing the level of phenylalanine in a subject in need thereof, comprising administering to the subject an effective amount of a phenylalanine dehydrogenase polypeptide, or a functional fragment thereof, wherein the phenylalanine dehydrogenase polypeptide or functional fragment thereof has at least about 80% sequence identity to SEQ ID NO: 1, and wherein the phenylalanine dehydrogenase polypeptide or functional fragment thereof is in a pharmaceutical formulation that is in a solid or semi-solid form, or contained within an artificial membrane.

9. The pharmaceutical formulation of claim 1 , wherein the phenylalanine dehydrogenase polypeptide, or the functional fragment thereof, comprises SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11.

10. A pharmaceutical formulation comprising a phenylalanine dehydrogenase polypeptide, or a functional fragment thereof, and a pharmaceutically-acceptable carrier, wherein the phenylalanine dehydrogenase polypeptide, or the functional fragment thereof, comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 1, and wherein the pharmaceutical formulation is in form of a tablet, suppository, pill, capsule, microsphere, powder, suspension, cream, ointment, or lotion.

11. The pharmaceutical formulation of claim 10 , wherein the phenylalanine dehydrogenase polypeptide, or the functional fragment thereof, comprises SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11.

12. The method of claim 8 , wherein the level of phenylalanine is reduced in the blood of the subject.

13. The method of claim 8 , wherein the subject has hyperphenylalaninemia.

14. The method of claim 8 , wherein the phenylalanine dehydrogenase polypeptide has at least about 95% sequence identity to SEQ ID NO: 1.

15. The method of claim 8 , wherein the phenylalanine dehydrogenase polypeptide, or functional fragment thereof, is administered orally.

16. The method of claim 8 , wherein the phenylalanine dehydrogenase polypeptide, or functional fragment thereof, is delivered to the intestinal tract of the subject, to the blood of the subject, or a combination thereof.

17. The method of claim 8 , further comprising administering an additional therapeutic agent to the subject.

18. The method of claim 17 , wherein the additional therapeutic agent is a phenylalanine ammonia lyase enzyme, a large neutral amino acid (LNAA), or nicotinamide adenine dinucleotide (NAD + ).

19. The method of claim 8 , wherein the subject has phenylketonuria (PKU).

20. The method of claim 8 , wherein the phenylalanine dehydrogenase polypeptide 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.

Assignees

• Childrens Nat Medical Ct

Inventors

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

Classifications

• C12Y403/01024

  Phenylalanine ammonia-lyase (4.3.1.24) · CPC title

• C12N9/0014

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

• A61K38/51

  Lyases (4) · CPC title

• A61K31/7084

  Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide · CPC title

• A61K31/195

  having an amino group · CPC title