Modeling severe neurological disorders in vivo for high-throughput drug discovery
The common prevalence of epilepsy and schizophrenia is common (2%) and of global concern. Both disorders are among the leading causes of disability, with severe symptoms having substantial impact on the quality of life for patients. Current treatment is limited to symptom-reducing drugs with severe side effects often taken during the patient´s lifetime. One third of epilepsy patients do not respond to current medication and their seizures remain uncontrolled. For schizophrenia, clinical management is limited to descriptive diagnostic criteria and outcome measures. Despite imposing an enormous economic societal burden, the mechanisms causing these diseases are largely unknown. As current medications act to suppress symptoms, there is an urgent need for therapies that can actually prevent or halt disease progression. Identifying these causes 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 the animal model of choice. There is growing recognition that novel insights into the causes and treatment of these debilitating conditions will be gained through neurodevelopmental models with alterations in neurological development, subsequently leading to clinically relevant phenotypes.There is an urgent need for the rapid functional evaluation of disease-associated genes. Similarly, there is a need for in vivo screening tools to identify drug-like compounds. Zebrafish are also an attractive model system for high-throughput analysis of behaviour. We aim to analyze the function of novel disease-associated genes involved in the development of drug resistant epilepsies and schizophrenia using genetic and chemical zebrafish models. Several models will be used to carry out screens for drug discovery. 18 models will be established and characterized requiring a total of 86616 animals throughout the study.
3Rs. By choosing the zebrafish, we are REPLACING rodents with a lower sentient vertebrate model, and whenever possible, performing tests at earlier stages of development, before they are capable of swimming freely, feeding by themselves and before brain regions involved in experiencing pain or discomfort have fully developed. We have also optimised all protocols to REFINE our assays in order to significantly reduce assay time and to REDUCE the number of animals required to obtain statistically significant results.
The degree of pain or discomfort was determined to range from sub-threshold to potentially severe (in cases where drug action cannot be predicted ahead of time). All animals will be monitored carefully during the experiments and euthanized prior to reaching defined humane endpoints. The majority of tests have been assessed at mild to moderate discomfort according to NORECOPA guidelines.
Societal Benefit. The proposed studies will not only identify potential new drugs for the approximated 2% of the world´s population who suffer from Epilepsy or Schizophrenia, but will also 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.
Our research program seeks to elucidate the mechanisms underlying epilepsy and schizophrenia using Zebrafish (Danio rerio) as the animal model of choice. There is growing recognition that novel insights into the causes and treatment of these debilitating conditions will be gained through neurodevelopmental models with alterations in neurological development, subsequently leading to clinically relevant phenotypes.There is an urgent need for the rapid functional evaluation of disease-associated genes. Similarly, there is a need for in vivo screening tools to identify drug-like compounds. Zebrafish are also an attractive model system for high-throughput analysis of behaviour. We aim to analyze the function of novel disease-associated genes involved in the development of drug resistant epilepsies and schizophrenia using genetic and chemical zebrafish models. Several models will be used to carry out screens for drug discovery. 18 models will be established and characterized requiring a total of 86616 animals throughout the study.
3Rs. By choosing the zebrafish, we are REPLACING rodents with a lower sentient vertebrate model, and whenever possible, performing tests at earlier stages of development, before they are capable of swimming freely, feeding by themselves and before brain regions involved in experiencing pain or discomfort have fully developed. We have also optimised all protocols to REFINE our assays in order to significantly reduce assay time and to REDUCE the number of animals required to obtain statistically significant results.
The degree of pain or discomfort was determined to range from sub-threshold to potentially severe (in cases where drug action cannot be predicted ahead of time). All animals will be monitored carefully during the experiments and euthanized prior to reaching defined humane endpoints. The majority of tests have been assessed at mild to moderate discomfort according to NORECOPA guidelines.
Societal Benefit. The proposed studies will not only identify potential new drugs for the approximated 2% of the world´s population who suffer from Epilepsy or Schizophrenia, but will also 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.
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FOTS 15469 - End Report
Overall, the majority of experiments described under FOTS 15469 (“Modeling severe
neurological disorders in vivo for high-throughput drug discovery”) have been
successful during the past four-year period. This is demonstrated by the list of publications (see
Reference list) since the work at the Centre for Molecular Medicine Norway (NCMM) was started.
Notably, the publication list included in this brief report does not include review articles or
publications from external collaborations (where the animal work was done elsewhere, and/or falls
under another FOTS permit, or under an equivalent animal research permit in another country).
Overall, we used fewer animals than originally applied for, due to project delays. Reasons for these
delays include: 1) Need for out-crossing of several mutant lines due to suspicion of additional
contaminating mutations after import from the Zebrafish International Resource Center (Oregon,
USA), 2) Slow development of some of the lines due to their genotype and 3) laboratory lockdown
due to the COVID19 pandemic.
We continue to analyze the function of novel disease-associated genes involved in the development
of drug resistant epilepsies and schizophrenia using genetic and chemical zebrafish models
according to the 3Rs. By choosing the zebrafish, we are REPLACING rodents with a lower sentient
vertebrate model, and whenever possible, performing tests at earlier stages of development, before
they are capable of swimming freely, feeding by themselves and before brain regions involved in
experiencing pain or discomfort have fully developed. We have also optimized all protocols to
REFINE our assays in order to significantly reduce assay time and to REDUCE the number of
animals required to obtain statistically significant results.
Overall, the majority of experiments described under FOTS 15469 (“Modeling severe
neurological disorders in vivo for high-throughput drug discovery”) have been
successful during the past four-year period. This is demonstrated by the list of publications (see
Reference list) since the work at the Centre for Molecular Medicine Norway (NCMM) was started.
Notably, the publication list included in this brief report does not include review articles or
publications from external collaborations (where the animal work was done elsewhere, and/or falls
under another FOTS permit, or under an equivalent animal research permit in another country).
Overall, we used fewer animals than originally applied for, due to project delays. Reasons for these
delays include: 1) Need for out-crossing of several mutant lines due to suspicion of additional
contaminating mutations after import from the Zebrafish International Resource Center (Oregon,
USA), 2) Slow development of some of the lines due to their genotype and 3) laboratory lockdown
due to the COVID19 pandemic.
We continue to analyze the function of novel disease-associated genes involved in the development
of drug resistant epilepsies and schizophrenia using genetic and chemical zebrafish models
according to the 3Rs. By choosing the zebrafish, we are REPLACING rodents with a lower sentient
vertebrate model, and whenever possible, performing tests at earlier stages of development, before
they are capable of swimming freely, feeding by themselves and before brain regions involved in
experiencing pain or discomfort have fully developed. We have also optimized all protocols to
REFINE our assays in order to significantly reduce assay time and to REDUCE the number of
animals required to obtain statistically significant results.