Forsøksdyr: Modeling severe neurological disorders in vivo for high-throughput drug discovery

Godkjenningsdato 01.07.2020

Godkjenningsperiode 01.07.2020-01.07.2024

Epilepsy and schizophrenia are common (2%) disorders and among the leading causes of disability, with severe symptoms having substantial impact on quality of life. Current (often life-lasting) treatment is limited to symptom-reducing drugs with severe side effects, and is ineffective in one-third of epilepsy patients. For schizophrenia, clinical management is limited to descriptive diagnostic criteria and outcome measures. Despite imposing enormous economic societal burdens, mechanisms causing these diseases are largely unknown. There is an urgent need for therapies preventing or halting disease progression, instead of treating symptoms. Identifying disease-mechanisms is imperative and may lead to major health benefits through the development of new treatment regimens.

Our research program seeks to elucidate the mechanisms underlying epilepsy and schizophrenia using Zebrafish (Danio rerio) as a model organism. Neurodevelopmental models with alterations in neurological development leading to clinically relevant phenotypes, grant novel insights into the causes and treatment of these debilitating conditions. There is an urgent need for the rapid functional evaluation of disease-associated genes, and for in vivo tools to screen drug-like compounds. Zebrafish are highly suited for high-throughput behaviour analysis. We will analyze the function of novel disease-associated genes involved in the development of drug-resistant epilepsies and schizophrenia using various zebrafish models. Several models will be used to carry out drug discovery screens. 60 models (32 stable genetic, 23 transient genetic, 5 chemical), established and newly-developed, will be characterized requiring 431,548 animals throughout the study. The models represent different diseases and different disease development mechanism, which is important to determine for which subset of epileptic or schizophrenic patients a novel therapeutic might be beneficial.

3Rs. By choosing zebrafish, we REPLACE rodents with a lower sentient vertebrate, and whenever possible, perform tests at earlier developmemtal stages, before they are capable of swimming freely or autonomous feeding and before brain regions involved in experiencing pain/discomfort have fully developed. We REFINED protocols to significantly reduce assay time and to REDUCE the number of animals required for statistically significant results. In the design of the projects, multiple models for one disorder are developed. Initial tests causing subthreshold levels of distress will determine the best model(s). This REFINEMENT in workflow REDUCES the number of animals required, as only the most robust models will be used to gain further insight into the disorders.

The degree of pain or discomfort was determined to range from sub-threshold to potentially severe (in cases where drug action cannot be predicted). Animals will be monitored throughout the experiments and euthanized prior to reaching defined humane endpoints. The majority of tests were assessed at mild to moderate discomfort (NORECOPA guidelines).

Societal Benefit. The proposed studies will identify potential new drugs for ~2% of the world´s population suffering from Epilepsy or Schizophrenia, and will serve as a pre-screen to test potential toxicities before entering clinical trials. Several models may enable the identification of Valproate alternatives, a drug used to treat Epilepsy, bipolar disorder and migraine headaches but is contraindicated in women of childbearing age due to the drug´s history of inducing birth defects.