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Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAH(enu2) mouse model of PKU

Phenylketonuria (PKU) is a genetic disease characterized by the inability to convert dietary phenylalanine to tyrosine by phenylalanine hydroxylase. Given the importance of gut microbes in digestion, a genetically engineered microbe could potentially degrade some ingested phenylalanine from the diet...

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Autores principales: Durrer, Katherine E., Allen, Michael S., Hunt von Herbing, Ione
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435137/
https://www.ncbi.nlm.nih.gov/pubmed/28520731
http://dx.doi.org/10.1371/journal.pone.0176286
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author Durrer, Katherine E.
Allen, Michael S.
Hunt von Herbing, Ione
author_facet Durrer, Katherine E.
Allen, Michael S.
Hunt von Herbing, Ione
author_sort Durrer, Katherine E.
collection PubMed
description Phenylketonuria (PKU) is a genetic disease characterized by the inability to convert dietary phenylalanine to tyrosine by phenylalanine hydroxylase. Given the importance of gut microbes in digestion, a genetically engineered microbe could potentially degrade some ingested phenylalanine from the diet prior to absorption. To test this, a phenylalanine lyase gene from Anabaena variabilis (AvPAL) was codon-optimized and cloned into a shuttle vector for expression in Lactobacillus reuteri 100-23C (pHENOMMenal). Functional expression of AvPAL was determined in vitro, and subsequently tested in vivo in homozygous PAH(enu2) (PKU model) mice. Initial trials of two PAH(enu2) homozygous (PKU) mice defined conditions for freeze-drying and delivery of bacteria. Animals showed reduced blood phe within three to four days of treatment with pHENOMMenal probiotic, and blood phe concentrations remained significantly reduced (P < 0.0005) compared to untreated controls during the course of experiments. Although pHENOMMenal probiotic could be cultured from fecal samples at four months post treatment, it could no longer be cultivated from feces at eight months post treatment, indicating eventual loss of the microbe from the gut. Preliminary screens during experimentation found no immune response to AvPAL. Collectively these studies provide data for the use of a genetically engineered probiotic as a potential treatment for PKU.
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spelling pubmed-54351372017-05-26 Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAH(enu2) mouse model of PKU Durrer, Katherine E. Allen, Michael S. Hunt von Herbing, Ione PLoS One Research Article Phenylketonuria (PKU) is a genetic disease characterized by the inability to convert dietary phenylalanine to tyrosine by phenylalanine hydroxylase. Given the importance of gut microbes in digestion, a genetically engineered microbe could potentially degrade some ingested phenylalanine from the diet prior to absorption. To test this, a phenylalanine lyase gene from Anabaena variabilis (AvPAL) was codon-optimized and cloned into a shuttle vector for expression in Lactobacillus reuteri 100-23C (pHENOMMenal). Functional expression of AvPAL was determined in vitro, and subsequently tested in vivo in homozygous PAH(enu2) (PKU model) mice. Initial trials of two PAH(enu2) homozygous (PKU) mice defined conditions for freeze-drying and delivery of bacteria. Animals showed reduced blood phe within three to four days of treatment with pHENOMMenal probiotic, and blood phe concentrations remained significantly reduced (P < 0.0005) compared to untreated controls during the course of experiments. Although pHENOMMenal probiotic could be cultured from fecal samples at four months post treatment, it could no longer be cultivated from feces at eight months post treatment, indicating eventual loss of the microbe from the gut. Preliminary screens during experimentation found no immune response to AvPAL. Collectively these studies provide data for the use of a genetically engineered probiotic as a potential treatment for PKU. Public Library of Science 2017-05-17 /pmc/articles/PMC5435137/ /pubmed/28520731 http://dx.doi.org/10.1371/journal.pone.0176286 Text en © 2017 Durrer et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Durrer, Katherine E.
Allen, Michael S.
Hunt von Herbing, Ione
Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAH(enu2) mouse model of PKU
title Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAH(enu2) mouse model of PKU
title_full Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAH(enu2) mouse model of PKU
title_fullStr Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAH(enu2) mouse model of PKU
title_full_unstemmed Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAH(enu2) mouse model of PKU
title_short Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAH(enu2) mouse model of PKU
title_sort genetically engineered probiotic for the treatment of phenylketonuria (pku); assessment of a novel treatment in vitro and in the pah(enu2) mouse model of pku
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435137/
https://www.ncbi.nlm.nih.gov/pubmed/28520731
http://dx.doi.org/10.1371/journal.pone.0176286
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