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Phenylalanine ammonia lyase, enzyme substitution therapy for phenylketonuria, where are we now?

Abstract：

:Phenylketonuria (PKU) is an autosomal recessive genetic disorder in which mutations in the phenylalanine-4-hydroxylase (PAH) gene result in an inactive enzyme (PAH, EC 1.14.16.1). The effect is an inability to metabolize phenylalanine (Phe), translating into elevated levels of Phe in the bloodstream (hyperphenylalaninemia). If therapy is not implemented at birth, mental retardation can occur. PKU patients respond to treatment with a low-phenylalanine diet, but compliance with the diet is difficult, therefore the development of alternative treatments is desirable. Enzyme substitution therapy with a recombinant phenylalanine ammonia lyase (PAL) is currently being explored. This enzyme converts Phe to the harmless metabolites, trans-cinnamic acid and trace ammonia. Taken orally and when non-absorbable and protected, PAL lowers plasma Phe in mutant hyperphenylalaninemic mouse models. Subcutaneous administration of PAL results in more substantial lowering of plasma and significant reduction in brain Phe levels, however the metabolic effect is not sustained following repeated injections due to an immune response. We have chemically modified PAL by pegylation to produce a protected form of PAL that possesses better specific activity, prolonged half-life, and reduced immunogenicity in vivo. Subcutaneous administration of pegylated molecules to PKU mice has the desired metabolic response (prolonged reduction in blood Phe levels) with greatly attenuated immunogenicity.

journal_name

Mol Genet Metab

journal_title

Molecular genetics and metabolism

authors

Sarkissian CN,Gámez A

doi

10.1016/j.ymgme.2005.06.016

subject

Has Abstract

pub_date

2005-12-01 00:00:00

pages

S22-6

eissn

1096-7192

issn

1096-7206

pii

S1096-7192(05)00238-6

journal_volume

86 Suppl 1

pub_type

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