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Human in vitro models for Fabry disease: new paths for unravelling disease mechanisms and therapies
Carla Borisch1, Thomas Thum1,2, Christian Bär1,2,3
1Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.
Abstract:
Fabry disease is a multi-organ disease, caused by mutations in the GLA gene and leading to a progressive accumulation of glycosphingolipids due to enzymatic absence or malfunction of the encoded alpha-galactosidase A. Since pathomechanisms are not yet fully understood and available treatments are not efficient for all mutation types and tissues, further research is highly needed. This research involves many different model types, with significant effort towards the establishment of an in vivo model. However, these models did not replicate the variety of symptoms observed in patients. As an alternative strategy, patient-derived somatic cells as well as patient-independent cell lines were used to model specific aspects of the disease in vitro. Fabry disease patients present different phenotypes according to the mutation and the level of residual enzyme activity, pointing to the necessity of personalized disease modeling. With the advent of induced pluripotent stem cells, the derivation of a multitude of disease-affected cell types became possible, even in a patient-specific and mutation-specific manner. Only recently, three-dimensional Fabry disease models were established that even more closely resemble the native tissue of investigated organs and will bring research closer to the in vivo situation. This review provides an overview of human in vitro models and their achievements in unravelling the Fabry disease pathomechanism as well as in elucidating current and future treatment strategies.
Insights
Fabry disease research needs better models. Patient-derived cells and 3D organoids offer promising in vitro approaches to understand this multi-organ condition and develop personalized treatments.
Area of Science:
- Biomedical Research
- Genetics
- Cell Biology
Background:
- Fabry disease is a genetic disorder caused by GLA gene mutations, leading to glycosphingolipid accumulation and multi-organ damage.
- Current in vivo models inadequately replicate the diverse patient phenotypes and disease mechanisms.
- Understanding Fabry disease requires advanced in vitro models that capture disease complexity.
Purpose of the Study:
- To review human in vitro models for Fabry disease research.
- To assess the utility of these models in understanding disease pathomechanisms.
- To evaluate their role in developing and testing treatment strategies.
Main Methods:
- Review of literature on in vitro models, including patient-derived somatic cells, cell lines, induced pluripotent stem cells (iPSCs), and 3D organoid models.
- Analysis of how these models replicate Fabry disease phenotypes and cellular defects.
- Evaluation of their application in studying disease progression and therapeutic interventions.
Main Results:
- Patient-derived cells and iPSCs enable personalized and mutation-specific disease modeling.
- Three-dimensional (3D) Fabry disease models more closely mimic native tissue environments.
- In vitro models have advanced the understanding of Fabry disease pathomechanisms and treatment efficacy.
Conclusions:
- Human in vitro models, particularly iPSCs and 3D organoids, are crucial for Fabry disease research.
- These models facilitate personalized approaches to understanding disease mechanisms and developing targeted therapies.
- Further development of in vitro models is essential for advancing Fabry disease treatment strategies.
