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Generation of improved human PAH for treatment of severe PKU by liver-directed gene replacement therapy

A residue and amino acid technology, applied in the field of variant phenylalanine hydroxylase polypeptides, can solve the problems of less effective neurological endpoints and lower blood Phe levels

Pending Publication Date: 2021-07-30
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This therapy significantly reduces blood Phe levels but appears to be less effective on neurological endpoints (Longo 2014)

Method used

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  • Generation of improved human PAH for treatment of severe PKU by liver-directed gene replacement therapy
  • Generation of improved human PAH for treatment of severe PKU by liver-directed gene replacement therapy
  • Generation of improved human PAH for treatment of severe PKU by liver-directed gene replacement therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach 1

[0198] Embodiment 1. A variant phenylalanine hydroxylase (PAH) polypeptide comprising two amino acid substitutions, wherein the amino acid is substituted at the site of M180, K199, S250, and G256 selected from the selected from the wild-type human PAH polypeptide. Place.

Embodiment approach 2

[0199] Embodiment 2. A variant phenylanine hydroxylase (PAH) polypeptide comprising three amino acid substitutions, wherein the amino acid substitution is located at the site of M180, K199, S250 and G256 selected from the group consisting of wild-type human PAH polypeptides. Place.

Embodiment approach 3

[0200] EXAMPLES 3. A variant phenylalanine hydroxylase (PAH) polypeptide comprising four amino acid substitutions, the amino acid substitution site M180, K199, S250, and G256 at the wild-type PAH polypeptide.

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PUM

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Abstract

Provided herein are variant phenylalanine hydroxylase (PAH) polypeptides which are more stable and have greater activity than wild-type human PAH. Also provided are methods to treat phenylketonuria (PKU) and / or to reduce levels of phenylalanine in an individual in need thereof. Further provided herein are expression cassettes, vectors (e.g., rAAV vectors), viral particles, pharmaceutical compositions and kits for expressing the variant PAH polypeptide in an individual in need thereof.

Description

[0001] Cross-reference [0002] The present application requires priority to the following applications: US Temporary Application Serial No. 62 / 744,944, submitted on October 12, 2018, which is incorporated herein by reference. [0003] Submission of ASCII text file sequence list [0004] The content of the ASCII text file submitted below is incorporated herein by reference: Computer readable form (CRF) sequence list (file name: 159792016640seqlist.txt, record date: October 16, 2019: 33KB) . Technical field [0005] The present disclosure relates to variant phenylalanine hydroxyase polypeptides. In some aspects, the present disclosure relates to compositions and methods for the treatment of phenyclone urine using genotype. Background technique [0006] Phenyltrunneuria (PKU) is a genetic flaw of hepaticralatine hydroxylase (PAH) of catalyzed phenylalanine (PHE) hydroxylated into tyrosine (TYR). This disease is the most common congenital defect in amino acid metabolism, in North A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/44C12N15/864
CPCC12N15/8645A61P3/00A61K38/443C12Y114/16001C12N9/0071C12N15/52C12N15/86A61K48/005C12N2750/14143A61K38/44A61K45/06A61K48/00
Inventor S·库斯迪奥-穆尔P·马纳瓦兰
Owner GENZYME CORP