Niklas Dahl – Heritable nervous system disorders: Novel mechanisms and drug target identification
Our aims are to:
- Identify novel gene variants associated with developmental and degenerative disorders, with a focus on the central nervous system (CNS).
- Model disease mechanisms and neuropathophysiology using induced pluripotent stem cell (iPSC) systems.
- Identify biomarkers associated with disorders of the CNS and establish conditions for screening using small compound libraries (drug screening).
Functional decoding of gene variants in the human genome is a major challenge. Our focus is to unravel mechanisms and the pathophysiology behind heritable disorders, mainly of traits involving the central nervous system (CNS). The long-term objective is to identify disease associated biomarkers that can be used in search for candidate compounds as a first step towards drug development.
Neurodevelopmental and neurodegenerative disorders comprise a heterogeneous group of conditions for which treatment options are limited. Furthermore, the progress in understanding disease mechanisms has been slow. The limited access to biological material and lack of model systems to faithfully recapitulate human neuropathophysiology have been two major bottlenecks. The advent of high throughput methods (e.g. next generation sequencing), induced pluripotent stem cell (iPSC) technologies combined with specific genome editing using CRISPR/Cas9 provide prerequisites to overcome the limitations.
Modeling nervous system disorders
To this end, we have established induced pluripotent stem cell (iPSC) culture systems that are differentiated into neuronal derivatives to model the pathophysiology behind selected heritable traits. The iPSCs are derived from patients with various genetic disorders of the CNS (e.g. epilepsy, Down syndrome, Alzheimer disease and specific forms of neurodevelopmental disorders), and from healthy individuals that can be gene edited to obtain isogenic lines with desired gene alterations.
Novel disease-associated biomarkers
Using high throughput analysis, we have identified several novel disease-associated biomarkers in neural models derived from iPSCs in 2D and in 3D (brain organoids). Some of the models are created and validated by CRISPR/Cas9 edited iPSC. Selected biomarkers will be adapted to screenable formats using neuronal stem cells and libraries of small compounds.
Read more about the project Disease modelling using induced pluripotent stem cells (iPSC).