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A novel Pah-exon1 deleted murine model of phenylalanine hydroxylase (PAH) deficiency.

Abstract：

:Phenylalanine hydroxylase (PAH) deficiency, colloquially known as phenylketonuria (PKU), is among the most common inborn errors of metabolism and in the past decade has become a target for the development of novel therapeutics such as gene therapy. PAH deficient mouse models have been key to new treatment development, but all prior existing models natively express liver PAH polypeptide as inactive or partially active PAH monomers, which complicates the experimental assessment of protein expression following therapeutic gene, mRNA, protein, or cell transfer. The mutant PAH monomers are able to form hetero-tetramers with and inhibit the overall holoenzyme activity of wild type PAH monomers produced from a therapeutic vector. Preclinical therapeutic studies would benefit from a PKU model that completely lacks both PAH activity and protein expression in liver. In this study, we employed CRISPR/Cas9-mediated gene editing in fertilized mouse embryos to generate a novel mouse model that lacks exon 1 of the Pah gene. Mice that are homozygous for the Pah exon 1 deletion are viable, severely hyperphenylalaninemic, accurately replicate phenotypic features of untreated human classical PKU and lack any detectable liver PAH activity or protein. This model of classical PKU is ideal for further development of gene and cell biologics to treat PKU.

journal_name

Mol Genet Metab

journal_title

Molecular genetics and metabolism

authors

Richards DY,Winn SR,Dudley S,Fedorov L,Rimann N,Thöny B,Harding CO

doi

10.1016/j.ymgme.2020.09.005

subject

Has Abstract

pub_date

2020-11-01 00:00:00

pages

306-315

issue

3

eissn

1096-7192

issn

1096-7206

pii

S1096-7192(20)30196-7

journal_volume

131

pub_type

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