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Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria
The development of therapeutics depends on predictions of clinical activity from pre-clinical data. We have previously described SYNB1618, an engineered bacterial therapeutic (synthetic biotic) for the treatment of Phenylketonuria (PKU), a rare genetic disease that leads to accumulation of plasma ph...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298439/ https://www.ncbi.nlm.nih.gov/pubmed/34294862 http://dx.doi.org/10.1038/s42003-021-02183-1 |
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author | Charbonneau, Mark R. Denney, William S. Horvath, Nicholas G. Cantarella, Pasquale Castillo, Mary J. Puurunen, Marja K. Brennan, Aoife M. |
author_facet | Charbonneau, Mark R. Denney, William S. Horvath, Nicholas G. Cantarella, Pasquale Castillo, Mary J. Puurunen, Marja K. Brennan, Aoife M. |
author_sort | Charbonneau, Mark R. |
collection | PubMed |
description | The development of therapeutics depends on predictions of clinical activity from pre-clinical data. We have previously described SYNB1618, an engineered bacterial therapeutic (synthetic biotic) for the treatment of Phenylketonuria (PKU), a rare genetic disease that leads to accumulation of plasma phenylalanine (Phe) and severe neurological complications. SYNB1618 consumes Phe in preclinical models, healthy human volunteers, and PKU patients. However, it remains unclear to what extent Phe consumption by SYNB1618 in the gastrointestinal tract lowers plasma Phe levels in PKU patients. Here, we construct a mechanistic model that predicts SYNB1618 function in non-human primates and healthy subjects by combining in vitro simulations and prior knowledge of human physiology. In addition, we extend a model of plasma Phe kinetics in PKU patients, in order to estimate plasma Phe lowering by SYNB1618. This approach provides a framework that can be used more broadly to define the therapeutic potential of synthetic biotics. |
format | Online Article Text |
id | pubmed-8298439 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82984392021-08-12 Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria Charbonneau, Mark R. Denney, William S. Horvath, Nicholas G. Cantarella, Pasquale Castillo, Mary J. Puurunen, Marja K. Brennan, Aoife M. Commun Biol Article The development of therapeutics depends on predictions of clinical activity from pre-clinical data. We have previously described SYNB1618, an engineered bacterial therapeutic (synthetic biotic) for the treatment of Phenylketonuria (PKU), a rare genetic disease that leads to accumulation of plasma phenylalanine (Phe) and severe neurological complications. SYNB1618 consumes Phe in preclinical models, healthy human volunteers, and PKU patients. However, it remains unclear to what extent Phe consumption by SYNB1618 in the gastrointestinal tract lowers plasma Phe levels in PKU patients. Here, we construct a mechanistic model that predicts SYNB1618 function in non-human primates and healthy subjects by combining in vitro simulations and prior knowledge of human physiology. In addition, we extend a model of plasma Phe kinetics in PKU patients, in order to estimate plasma Phe lowering by SYNB1618. This approach provides a framework that can be used more broadly to define the therapeutic potential of synthetic biotics. Nature Publishing Group UK 2021-07-22 /pmc/articles/PMC8298439/ /pubmed/34294862 http://dx.doi.org/10.1038/s42003-021-02183-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Charbonneau, Mark R. Denney, William S. Horvath, Nicholas G. Cantarella, Pasquale Castillo, Mary J. Puurunen, Marja K. Brennan, Aoife M. Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria |
title | Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria |
title_full | Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria |
title_fullStr | Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria |
title_full_unstemmed | Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria |
title_short | Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria |
title_sort | development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298439/ https://www.ncbi.nlm.nih.gov/pubmed/34294862 http://dx.doi.org/10.1038/s42003-021-02183-1 |
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