Functional studies using a personalized approach to treat phenylketonuria patients

• Applicant: Polina Gundorova, Ph.D.
• Subject Area: Human Genetics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545592461

Phenylketonuria (PKU) is the most common inborn metabolic disorder, and this project aims to contribute to ongoing research efforts to improve our understanding and management of this condition. Significant data has been gathered on the population structure of PAH gene mutation spectrums, providing a solid foundation for further investigation. Identifying and studying the most common population-specific PAH genotypes can provide invaluable insights into the mechanisms of this disease. PAH pathogenic variants create a wide range of patient phenotypes, each with unique treatment requirements. Unfortunately, studying the function of the damaged protein in PKU patients' samples is not feasible, as the PAH enzyme is selectively expressed in liver tissue. To address this challenge, this project focuses on the functional studies of PAH genotypes using an in situ model. Another gap concerns splice variants of the PAH that are understudied and their effect on the function of the enzyme remains unclear. By establishing and performing the mini-gene assay for PAH splice variants, changes caused by the variant at the mRNA level can be identified. This knowledge opens up the possibility of using molecular tools and techniques for further analysis of the variant protein. A translational approach is being taken to move from in vitro experiments with single variants of the PAH enzyme to mimicking patients' genotypes in situ and eventually applying the findings in vivo. During the in situ phase of the project, we will use a PAH activity landscapes assay to evaluate the mutual influence of various substrate and cofactor concentrations on PAH enzyme activity. Patients at Kinder-UKE clinic will receive personalized treatment recommendations, as will patients with the most common PAH genotypes from studied populations. As part of the collaboration process, PAH activity landscapes will be performed for PAH genotypes from several countries in Eastern Europe, South America, and Asia. Overall, this translational approach holds great promise for improving patient outcomes and developing more effective treatments for PKU. Personalized function studies represent the next stage in the development of molecular-genetic diagnostic processes for inborn genetic diseases. It's essential that modern healthcare takes advantage of the latest research findings generated by scientists using the newest techniques, in order to benefit patients. Through this project, we aim to bridge the gap between the lab and clinic, making our research results available to both the scientific community and the public. By doing so, we hope to pave the way for more personalized, effective treatments for patients with inborn genetic diseases.

• DFG Programme: Research Grants