Comparison of adeno-associated virus pseudotype 1, 2, and 8 vectors administered by intramuscular injection in the treatment of murine phenylketonuria.

Human Gene Therapy
Alexandre RebuffatBeat Thöny

Abstract

Phenylketonuria (PKU) is caused by hepatic phenylalanine hydroxylase (PAH) deficiency and is associated with systemic accumulation of phenylalanine (Phe). Previously we demonstrated correction of murine PKU after intravenous injection of a recombinant type 2 adeno-associated viral vector pseudotyped with type 8 capsid (rAAV2/8), which successfully directed hepatic transduction and Pah gene expression. Here, we report that liver PAH activity and phenylalanine clearance were also restored in PAH-deficient mice after simple intramuscular injection of either AAV2 pseudotype 1 (rAAV2/1) or rAAV2/8 vectors. Serotype 2 AAV vector (rAAV2/2) was also investigated, but long-term phenylalanine clearance has been observed only for pseudotypes 1 and 8. Therapeutic correction was shown in both male and female mice, albeit more effectively in males, in which correction lasted for the entire period of the experiment (>1 year). Although phenylalanine levels began to rise in female mice at about 8-10 months after rAAV2/8 injection they remained only mildly hyperphenylalaninemic thereafter and subsequent supplementation with synthetic tetrahydrobiopterin resulted in a transient decrease in blood phenylalanine. Alternatively, subsequent administra...Continue Reading

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Citations

Feb 13, 2010·Journal of Inherited Metabolic Disease·Beat Thöny
Nov 19, 2010·Journal of Inherited Metabolic Disease·Cary O Harding, Nenad Blau
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Oct 15, 2020·Molecular Genetics and Metabolism·Daelyn Y RichardsCary O Harding

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Methods Mentioned

BETA
transfection
electrophoresis
PCR
transgenic

Software Mentioned

GraphPad Prism
GraphPad
NIH Image

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