UCD Translational Center
Universitäts-Kinderspital Zürich
Lenggstrasse 30
8008 Zürich
Universitäts-Kinderspital Zürich
Lenggstrasse 30
8008 Zürich
Urea Cycle Disorders (UCDs)
Urea Cycle Disorders (UCDs) are a group of rare, monogenic disorders that affect the ability of the urea cycle pathway to clear ammonia from the body and to maintain an efficient redox metabolism in the mitochondria. Ammonia is a toxic byproduct of protein metabolism, and alterations in the urea cycle can lead to its accumulation in the blood, resulting in hyperammonemia. Additionally, UCDs can lead to metabolic disturbances that cause lifelong complications. Our research aims at improving diagnosis and developing new therapeutic approaches for UCDs. Key areas of investigation include:
- Diagnostics including functional pathway analysis
- Treatment strategies
- Gene therapies
- Research methods and model systems
UREA CYCLE DISORDERS TRANSLATIONAL CENTER UNIVERSITÄT ZURICH - CITRIN FOUNDATION
Urea Cycle Disorders Translational Center aims to change the landscape of research by translating innovative therapies from the laboratory bench to the clinic, focusing on providing new treatments perspectives that could help, give hope and improve the quality of life of patients suffering from any of the urea cycle disorders. The center has been stablished through the collaboration of the University of Zürich & Citrin Foundation, under the auspices of the UZH Foundation and hosted at the Children’s Research Center of the University Children’s Hospital Zurich.
UCD TRANSLATIONAL RESEARCH PROJECTS
Biomarker Discovery
The main goal of this study is to identify circulating biomarkers that are specific to Citrin Deficiency using both targeted and untargeted metabolomics, proteomics, lipidomics, and transcriptomics analysis of collected blood samples.
Study Details | Multi-omics Study in Citrin Deficiency | ClinicalTrials.gov
Gene Therapy
We are using CRISPR-based approaches, such as prime editing, to correct genetic mutations that cause Citrin Deficiency in liver cells. These studies pave the way for clinical trials that can lead to a cure for Citrin Deficiency.
Liver Metabolic Function Study
It is unclear how nutrients are processed to produce energy in patients with Citrin Deficiency. Using stable isotope tracers in vivo, we are able to track how nutrients are metabolized in patients and how their liver metabolic functions are altered.
Defining Disease Metrics for Citrin Deficiency
It is important to be able to measure the severity of Citrin Deficiency. For this purpose we are defining scoring systems that cover physical health and also Patient Reported Outcome Measures (PROMs). Patients’ perspectives are vital for providing patient-centered healthcare and interventions.
Diagnostics
We are identifying novel biomarkers to diagnose UCDs more quickly and accurately and assess the biochemical state of patients using pathway flux studies.
- Isotope tracing of urea and urea cycle intermediates
- Activity assay of key UCD enzymes – OTC and CPS1
- Metabolomic approaches to identify new biomarkers
Treatment
We are investigating how anaplerotic agents such as nutritional supplements can support the formation of urea and the energy metabolism in cells with a dysfunctional urea cycle.
- Supplementation of citrulline, arginine, di-peptides
- Pharmacological screening to identify novel treatments for citrin deficiency
Gene therapy
There is currently no cure for UCDs. We are developing therapies to correct the underlying genetic defect of UCDs to restore a normal liver function in patients. We are currently exploring innovative new approaches to treat OTC deficiency, one of the more common UCDs.
- Novel CRISPR based technologies like prime and base editing
- Epigenetic reactivation of wildtype OTC on the silenced X chromosome
Research methods
To investigate UCDs, accurate model systems are needed. We are working to define cell lines or animal models that faithfully recapitulate the metabolic defects observed in UCD patients.
- Functional characterization of hepatocyte-like cells derived from HepaRG, iPSCs and other stem cell progenitors
- In vivo and ex vivo approaches in mice
