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 traits of the central nervous system.
  • Model novel disease progression using induced pluripotent stem cell (iPSC) systems and identify neuropathophysiological mechanisms.
  • Utilise biomarkers associated with central nervous system (CNS) disorders to establish screening conditions 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 in 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. Major obstructive factors have been the limited access to biological material and model systems to faithfully recapitulate human neuropathophysiology.

Possibilities to overcome these problems have come from the advent of high throughput methods (e.g. next generation sequencing) and induced pluripotent stem cell (iPSC) technologies combined with specific genome editing using CRISPR/Cas9.

Modeling nervous system disorders

To model the pathophysiology behind heritable traits we have established induced pluripotent stem cell (iPSC) culture systems that are differentiated into mature nerve cells. The iPSCs are derived from patients with various genetic disorders of the CNS (e.g. epilepsy, Down syndrome, Alzheimer’s 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 (called 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 Identification of novel gene variants associated with heritable phenotypes

Read more about Disease modeling using induced pluripotent stem cells (iPSC)

Microscope image of astrocyte differentated from induced pluripotent stem cells
An astrocyte (green) after 30 days of differentiation of induced pluripotent stem cells (iPSC), established from an individual with Down syndrome. The purpose is to study the central nervous system neuropathophysiology in the condition.