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Use of an adeno‐associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model
Author(s) -
Kaiser Robert A.,
Weber Nicholas D.,
TriguerosMotos Laia,
Allen Kari L.,
Martinez Michael,
Cao William,
VanLith Caitlin J.,
Hillin Lori G.,
Douar Anne,
GonzálezAseguinolaza Gloria,
Aldabe Rafael,
Lillegard Joseph B.
Publication year - 2021
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12392
Subject(s) - adeno associated virus , phenylalanine hydroxylase , tyrosinemia , genetic enhancement , inborn error of metabolism , biology , gene , phenylalanine , gene delivery , vector (molecular biology) , microbiology and biotechnology , medicine , recombinant dna , endocrinology , genetics , biochemistry , tyrosine , amino acid
Phenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene ( PAH ). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno‐associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon‐optimized human PAH gene, with or without an intron spacer, to the Pah enu2 mouse model of PKU. Dose‐dependent transduction of the liver and expression of PAH mRNA were present with both vectors, resulting in significant and durable reduction of circulating phenylalanine, reaching near control levels in males. Coat color of treated Pah enu2 mice reflected an increase in pigmentation from brown to the black color of control animals, further indicating functional restoration of phenylalanine metabolism and its byproduct melanin. There were no adverse effects associated with administration of AAV up to 5 × 10 12 VG/kg, the highest dose tested. Only minor and/or transient variations in some liver enzymes were observed in some of the AAV‐dosed animals which were not associated with pathology findings in the liver. Finally, there was no impact on cell turnover or apoptosis as evaluated by Ki‐67 and TUNEL staining, further supporting the safety of this approach. This study demonstrates the therapeutic potential of AAV Anc80 to safely and durably cure PKU in a mouse model, supporting development for clinical consideration.