UZH-Logo

Maintenance Infos

Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle


Thöny, B (2010). Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle. Journal of Inherited Metabolic Disease, 33(6):677-680.

Abstract

Current therapy for phenylketonuria (PKU) consists of life-long dietary restriction of phenylalanine (Phe), which presents problems of adherence for patients. Alternative therapies under investigation include, among others, the use of gene therapy to provide copies of wild-type, non-mutant, phenylalanine hydroxylase (PAH) enzyme. Expression of PAH in both liver (the usual metabolic source of this enzyme) and skeletal muscle is under investigation. Liver gene therapy, using a viral vector based on the adeno-associated viruses (AAVs), provided effective clearance of serum Phe that was sustained for 1 year in some mice. In order for PAH expression to be effective in skeletal muscle, the essential metabolic cofactor, tetrahydrobiopterin (BH(4)), must also be provided, either by supplementation or gene therapy. Both these approaches were effective. When transgenic PKU mice that constitutively expressed PAH in muscle were given intraperitoneal supplementation with BH(4), this produced (transient) effective clearance of Phe to normal levels. In addition, use of an AAV vector containing the genes for PAH, and for two key synthetic enzymes for BH(4), provided substantial and long-lasting correction (more than 1 year) of blood Phe levels when injected into skeletal muscle of PKU mice. These two strategies provide promising treatment alternatives for the management of PKU in patients.

Current therapy for phenylketonuria (PKU) consists of life-long dietary restriction of phenylalanine (Phe), which presents problems of adherence for patients. Alternative therapies under investigation include, among others, the use of gene therapy to provide copies of wild-type, non-mutant, phenylalanine hydroxylase (PAH) enzyme. Expression of PAH in both liver (the usual metabolic source of this enzyme) and skeletal muscle is under investigation. Liver gene therapy, using a viral vector based on the adeno-associated viruses (AAVs), provided effective clearance of serum Phe that was sustained for 1 year in some mice. In order for PAH expression to be effective in skeletal muscle, the essential metabolic cofactor, tetrahydrobiopterin (BH(4)), must also be provided, either by supplementation or gene therapy. Both these approaches were effective. When transgenic PKU mice that constitutively expressed PAH in muscle were given intraperitoneal supplementation with BH(4), this produced (transient) effective clearance of Phe to normal levels. In addition, use of an AAV vector containing the genes for PAH, and for two key synthetic enzymes for BH(4), provided substantial and long-lasting correction (more than 1 year) of blood Phe levels when injected into skeletal muscle of PKU mice. These two strategies provide promising treatment alternatives for the management of PKU in patients.

Citations

6 citations in Web of Science®
4 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

3 downloads since deposited on 17 Jan 2011
0 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2010
Deposited On:17 Jan 2011 10:10
Last Modified:05 Apr 2016 14:35
Publisher:Springer
ISSN:0141-8955
Funders:Anna Müller Grocholsky Foundation , Hartmann Müller Foundation, Stiftung für wissenschaftliche Forschung an der Universität Zürich, Novartis Stiftung, Swiss National Science Foundation
Publisher DOI:https://doi.org/10.1007/s10545-010-9044-3
PubMed ID:20151201
Permanent URL: https://doi.org/10.5167/uzh-42424

Download

[img]
Filetype: PDF - Registered users only
Size: 116kB
View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations