Metabolic engineering as therapy for inborn errors of metabolism - Development of mice with phenylalanine hydroxylase expression in muscle

Cary Harding, K. Wild, D. Chang, A. Messing, J. A. Wolff

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Treatment of many inherited liver enzyme deficiencies the removal of toxic intermediate metabolites from the blood of affected individuals. We propose that circulating toxins can be adequately cleared and disease phenotype influenced by enzyme expressed in tissues other than the liver. Phenylalanine hydroxylase (PAH) activity was expressed in skeletal and cardiac muscle of transgenic mice which carried the PAH cDNA under the transcriptional control of the mouse muscle creatine kinase promoter. Muscle PAH-expressing mice were bred to liver PAH-deficient, hyperphenylalaninemic mice to yield progeny that lack PAH activity in liver but express PAH in muscle. These mice exhibited hyperphenylalaninemia at baseline, but serum phenylalanine levels decreased significantly when the mice were supplemented with tetrahydrobiopterin (BH4), a required cofactor for PAH. This is the first demonstration that a liver-specific enzyme, when expressed in a heterologous tissue and supplied with necessary cofactors, can effectively clear toxic metabolites from the circulation of individuals with inherited enzyme deficiency. This result suggests that gene therapy targeted to heterologous tissues, such as muscle, will be effective in the treatment of selected inborn errors of metabolism.

Original languageEnglish (US)
Pages (from-to)677-683
Number of pages7
JournalGene Therapy
Volume5
Issue number5
StatePublished - 1998
Externally publishedYes

Fingerprint

Phenylalanine Hydroxylase
Metabolic Engineering
Inborn Errors Metabolism
Muscles
Liver
Poisons
Enzymes
Therapeutics
MM Form Creatine Kinase
Phenylketonurias
Phenylalanine
Genetic Therapy
Transgenic Mice
Myocardium
Skeletal Muscle
Complementary DNA
Phenotype
Serum

Keywords

  • Inborn errors of metabolism
  • Muscle
  • Phenylketonuria

ASJC Scopus subject areas

  • Genetics

Cite this

Metabolic engineering as therapy for inborn errors of metabolism - Development of mice with phenylalanine hydroxylase expression in muscle. / Harding, Cary; Wild, K.; Chang, D.; Messing, A.; Wolff, J. A.

In: Gene Therapy, Vol. 5, No. 5, 1998, p. 677-683.

Research output: Contribution to journalArticle

@article{037effc8ea8341569217deb270ca89e2,
title = "Metabolic engineering as therapy for inborn errors of metabolism - Development of mice with phenylalanine hydroxylase expression in muscle",
abstract = "Treatment of many inherited liver enzyme deficiencies the removal of toxic intermediate metabolites from the blood of affected individuals. We propose that circulating toxins can be adequately cleared and disease phenotype influenced by enzyme expressed in tissues other than the liver. Phenylalanine hydroxylase (PAH) activity was expressed in skeletal and cardiac muscle of transgenic mice which carried the PAH cDNA under the transcriptional control of the mouse muscle creatine kinase promoter. Muscle PAH-expressing mice were bred to liver PAH-deficient, hyperphenylalaninemic mice to yield progeny that lack PAH activity in liver but express PAH in muscle. These mice exhibited hyperphenylalaninemia at baseline, but serum phenylalanine levels decreased significantly when the mice were supplemented with tetrahydrobiopterin (BH4), a required cofactor for PAH. This is the first demonstration that a liver-specific enzyme, when expressed in a heterologous tissue and supplied with necessary cofactors, can effectively clear toxic metabolites from the circulation of individuals with inherited enzyme deficiency. This result suggests that gene therapy targeted to heterologous tissues, such as muscle, will be effective in the treatment of selected inborn errors of metabolism.",
keywords = "Inborn errors of metabolism, Muscle, Phenylketonuria",
author = "Cary Harding and K. Wild and D. Chang and A. Messing and Wolff, {J. A.}",
year = "1998",
language = "English (US)",
volume = "5",
pages = "677--683",
journal = "Gene Therapy",
issn = "0969-7128",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Metabolic engineering as therapy for inborn errors of metabolism - Development of mice with phenylalanine hydroxylase expression in muscle

AU - Harding, Cary

AU - Wild, K.

AU - Chang, D.

AU - Messing, A.

AU - Wolff, J. A.

PY - 1998

Y1 - 1998

N2 - Treatment of many inherited liver enzyme deficiencies the removal of toxic intermediate metabolites from the blood of affected individuals. We propose that circulating toxins can be adequately cleared and disease phenotype influenced by enzyme expressed in tissues other than the liver. Phenylalanine hydroxylase (PAH) activity was expressed in skeletal and cardiac muscle of transgenic mice which carried the PAH cDNA under the transcriptional control of the mouse muscle creatine kinase promoter. Muscle PAH-expressing mice were bred to liver PAH-deficient, hyperphenylalaninemic mice to yield progeny that lack PAH activity in liver but express PAH in muscle. These mice exhibited hyperphenylalaninemia at baseline, but serum phenylalanine levels decreased significantly when the mice were supplemented with tetrahydrobiopterin (BH4), a required cofactor for PAH. This is the first demonstration that a liver-specific enzyme, when expressed in a heterologous tissue and supplied with necessary cofactors, can effectively clear toxic metabolites from the circulation of individuals with inherited enzyme deficiency. This result suggests that gene therapy targeted to heterologous tissues, such as muscle, will be effective in the treatment of selected inborn errors of metabolism.

AB - Treatment of many inherited liver enzyme deficiencies the removal of toxic intermediate metabolites from the blood of affected individuals. We propose that circulating toxins can be adequately cleared and disease phenotype influenced by enzyme expressed in tissues other than the liver. Phenylalanine hydroxylase (PAH) activity was expressed in skeletal and cardiac muscle of transgenic mice which carried the PAH cDNA under the transcriptional control of the mouse muscle creatine kinase promoter. Muscle PAH-expressing mice were bred to liver PAH-deficient, hyperphenylalaninemic mice to yield progeny that lack PAH activity in liver but express PAH in muscle. These mice exhibited hyperphenylalaninemia at baseline, but serum phenylalanine levels decreased significantly when the mice were supplemented with tetrahydrobiopterin (BH4), a required cofactor for PAH. This is the first demonstration that a liver-specific enzyme, when expressed in a heterologous tissue and supplied with necessary cofactors, can effectively clear toxic metabolites from the circulation of individuals with inherited enzyme deficiency. This result suggests that gene therapy targeted to heterologous tissues, such as muscle, will be effective in the treatment of selected inborn errors of metabolism.

KW - Inborn errors of metabolism

KW - Muscle

KW - Phenylketonuria

UR - http://www.scopus.com/inward/record.url?scp=0031834511&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031834511&partnerID=8YFLogxK

M3 - Article

C2 - 9797873

AN - SCOPUS:0031834511

VL - 5

SP - 677

EP - 683

JO - Gene Therapy

JF - Gene Therapy

SN - 0969-7128

IS - 5

ER -