Research

Stem cell derived models for rare monogenic disease

Induced pluripotent stem (iPS) cells are somatic cells that have been reprogrammed back to a pluripotent stem cell stage. Similarly to embryonic stem cells, they can differentiate to any cell type found in the adult body. Since they can be derived from patients, they have opened up new ways to use patient cells in research. They allow mechanistic studies in living patient neurons or cardiac cells, or any other cell type that would otherwise not be available for research purposes.

We are developing novel stem cell based model systems for human rare monogenic disorders.

Progressive myoclonic epilepsy

Progressive myoclonus epilepsies (PMEs) are a heterogeneous group of rare genetic disorders defined by the combination of action myoclonus, epileptic seizures and progressive neurologic deterioration.

Unverricht-Lundborg disease i.e. progressive myoclonus epilepsy type 1 (EPM1) is the most common PME. It is an autosomal recessive disorder that leads to the onset of neurodegeneration between 6 and 15 years of age. EPM1 patients suffer from photo-sensitive seizures, stimulus-sensitive myoclonus, nocturnal myoclonic seizures, ataxia and dysarthria.

Loss-of-function mutations in the Cystatin B (CSTB) gene underly EPM1. The detailed neuropathological mechanisms leading from the CSTB mutations to the disease manifestations are still unknown. Thus no curative treatments exist and current treatment strategies only rely on relieving symptoms. While the epileptic seizures can be controlled with antiseizure medication, the myoclonus causes major disability in patients and progression of the disease leads to premature mortality. Thus, there is a need for novel treatments for EPM1 patients.

CSTB knockout mice have provided valuable information on EPM1 disease mechanisms, however, as typical for neurological disease, their suitability especially in drug trials is limited and human cell based models are needed to complement the mouse trials. We are developing a human cell based platform for preclinical research on EPM1. The platform can be utilized to study disease mechanisms as well as in initial preclinical treatment trials.

Mitochondrial disease

Mitochondria play a role in several human disorders, and since both nuclear and mitochondrial DNA encode mitochondrial proteins, mutations in both genomes can lead to mitochondrial disorders. The manifestations of these diseases vary from infantile multisystem disorders to adult-onset myopathies and neurodegeneration, and indeed, mitochondrial disease can occur in any organ-system, with any age of onset. The most commonly affected tissues are those that need most energy, namely the brain and the heart.

The pathological mechanisms underlying mitochondrial disease mechanisms are largely unknown. This is mainly due to the lack of proper experimental model systems. Introduction of exogenous DNA to mitochondria has been unsuccessful, preventing generation of animal models. Stem cell-derived technology allows optimal usage of patient material and generation of in vitro models of those cell types that are relevant for the disease phenotype.

We are especially interested in why the same mutation in mitochondrial DNA can lead to very different phenotype in different patients. To investigate this we are developing cardiac and neuroal models from patients with mtDNA mutations.

Mitochondria and mtDNA in stem cells

Mitochondria are cellular powerplants that produce energy in the form of ATP for the cells needs. In addition to the energy production, mitochondria serve fundamental roles in cellular signaling, generating and regulating reactive oxygen species (ROS), buffering cytosolic calcium levels and regulating apoptosis. Mitochondrial function also regulates cellular fate choices and is especially important in stem cells regulating quiescence, activation, self-renewal and differentiation of the stem cell pools.

Mitochondria possess multiple copies of their own DNA and are under dual genetic control by nuclear genome and their own genome. We are interested in the maintenance of the mtDNA and the importance of mtDNA integrity in regulating aging and self-renewal of stem cell pools.