Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model

被引:11
作者
Kaiser, Robert A. [1 ,2 ]
Weber, Nicholas D. [3 ]
Trigueros-Motos, Laia [3 ]
Allen, Kari L. [2 ]
Martinez, Michael [4 ]
Cao, William [2 ]
VanLith, Caitlin J. [2 ]
Hillin, Lori G. [2 ]
Douar, Anne [5 ]
Gonzalez-Aseguinolaza, Gloria [3 ,6 ,7 ]
Aldabe, Rafael [6 ]
Lillegard, Joseph B. [1 ,2 ,8 ]
机构
[1] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA
[2] Mayo Clin, Dept Surg, 200 First St SW, Rochester, MN 55905 USA
[3] Vivet Therapeut S L, Pamplona, Spain
[4] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA
[5] Vivet Therapeut SAS, Paris, France
[6] CIMA Univ Navarra, Div Gene Therapy & Regulat Gene Express, Edificio CIMA,Av Pio XII 55, Pamplona 31008, Spain
[7] Inst Invest Sanitaria Navarra IdISNA, Pamplona, Spain
[8] Pediat Surg Associates, Minneapolis, MN USA
关键词
adeno-associated virus (AAV) vector; Anc80; gene therapy; inborn error of metabolism; phenylketonuria; GENE-THERAPY; LIVER TRANSDUCTION; MICE; HYPERPHENYLALANINEMIA; DEFINITION; EXPRESSION; VECTORS; GENOMES;
D O I
10.1002/jimd.12392
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 x 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.
引用
收藏
页码:1369 / 1381
页数:13
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