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J. Biol. Chem., Vol. 282, Issue 32, 23402-23409, August 10, 2007

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A Novel Approach for Enzyme Replacement Therapy

THE USE OF PHENYLALANINE HYDROXYLASE-BASED FUSION PROTEINS FOR THE TREATMENT OF PHENYLKETONURIA^*

From the Department of Cellular Biochemistry and Human Genetics, Faculty of Medicine, Hebrew University, Ein-Kerem, Jerusalem 91120, Israel

Metabolic diseases arise from mutations in key enzymes of major metabolic pathways. One promising approach for the treatment of such diseases is based on the administration of a wild-type enzyme to substitute the activity of the impaired enzyme by the use of enzyme replacement therapy, yet it is important to deliver this enzyme to the specific deficient tissue. We suggest a new concept for the treatment of metabolic diseases using fusion proteins. We examined the feasibility of this concept in the well characterized metabolic disease, phenylketonuria (PKU), which results from a mutation in the liver enzyme phenylalanine hydroxylase (PAH). PAH is a key enzyme in the metabolic pathway of phenylalanine. Deficiency in PAH leads to high and persistent levels of this amino acid in the plasma of PKU patients, causing permanent neurological damage. Currently a low protein diet is still considered the only effective treatment for most PKU patients. To restore PAH activity in the liver of PKU patients, we constructed PAH-based fusion proteins with delivery moieties based on the HIV-transactivator of transcription peptide, and fragments of human hepatocyte growth factor aiming to specifically target PAH to the liver. We show that these new fusion proteins can be delivered into a variety of human liver cell lines and retain PAH activity after being internalized. We also show that plasma phenylalanine levels were dramatically lowered in mice treated with PAH-based fusion proteins after intravenous administration. We therefore suggest an alternative concept for the treatment of PKU using targeted fusion proteins, which may also be applied to the treatment of other metabolic diseases.

Received for publication, April 23, 2007 , and in revised form, June 11, 2007.

^* This work was supported by the Israel Science Foundation (Grant 035358). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Tel.: 972-2-675-7465; Fax: 972-2-641-5848; E-mail: hayalg{at}md.huji.ac.il.

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