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Synthetic closed-loop gene circuit for phenylalanine regulation
Silvia Galvan1, Yu-Qing Xie1, Ana P Teixeira1
1Department of Biosystems Science and Engineering, ETH Zurich, Klingelbergstrasse 48, Basel CH-4056, Switzerland.
Nucleic Acids Research
|November 5, 2025
Summary
Engineered cells (PRO) can sense and degrade excess phenylalanine, a key issue in phenylketonuria (PKU). This closed-loop system shows promise for treating metabolic diseases by restoring normal amino acid levels.
Area of Science:
- Synthetic biology
- Genetic engineering
- Cell-based therapies
Background:
- Cell-based therapies offer potential for chronic disease treatment.
- Closed-loop systems that self-regulate in response to biomarkers are highly desirable.
- Phenylketonuria (PKU) is a metabolic disorder characterized by elevated phenylalanine levels.
Purpose of the Study:
- To engineer a cell-autonomous genetic system (PRO) for sensing and degrading phenylalanine.
- To develop a self-regulating therapeutic system for PKU treatment.
- To demonstrate the efficacy of PRO cells in reducing phenylalanine levels in vitro and in vivo.
Main Methods:
- Engineered a transcriptional switch using human phenylalanine hydroxylase regulatory domain.
- Optimized the sensing module via random mutagenesis for phenylalanine responsiveness.
- Expressed phenylalanine-degrading enzymes in engineered human cells (PRO cells).
- Tested PRO cell efficacy in human whole blood and in a PKU mouse model.
Main Results:
- PRO cells effectively sensed and degraded excess phenylalanine in a dose-dependent manner.
- Microencapsulated PRO cells normalized phenylalanine levels in human whole blood.
- Alginate-encapsulated PRO cells significantly reduced blood phenylalanine in PKU mice.
Conclusions:
- Synthetic self-regulating systems are promising for treating metabolic diseases.
- PRO cells demonstrate potential as a novel therapeutic for phenylketonuria.
- Genetic programming of cells offers a viable strategy for next-generation therapies.
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