Scientific publications

Use of an AAV serotype Anc80 to provide durable cure of phenylketonuria in a mouse model

Nov 1, 2021 | Magazine: Journal of Inherited Metabolic Disease

Robert A Kaiser, Nicholas D Weber, Laia Trigueros-Motos, Kari L Allen, Michael Martinez, William Cao, Caitlin J VanLith, Lori G Hillin, Anne Douar, Gloria González-Aseguinolaza, Rafael Aldabe, Joseph B Lillegard


Phenylketonuria 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 viral (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 Pahenu2 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 Pahenu2 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 5x1012 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. This article is protected by copyright. All rights reserved.

CITATION  J Inherit Metab Dis. 2021 Nov;44(6):1369-1381.  doi: 10.1002/jimd.12392.  Epub 2021 Aug 19.