Development of a Drosophila-based platform to replace and reduce animal experimentation in epilepsy research
Lead Research Organisation:
King's College London
Department Name: Neuroscience
Abstract
Epilepsy is a devastating disorder of the nervous system that affects 1 in 100 people and poses a heavy burden of patients, relatives and the NHS. While some anti-epileptic medicines exist, they do not work for all patients and they only keep the symptoms at minimum level, without being able to cure the disease.
There are several causes of epilepsy, and scientists are beginning to understand rare forms of epilepsy that are hereditary and are associated with other disorders of sleep and movement. While each single case is rare, altogether hereditary epilepsies are a big portion of the total epileptic population.
Hereditary epilepsies are due to mutation in genes and scientists need to study these genes in small animals to understand how they work and cause epilepsy. This is often done in mice, however studying genes in mice is slow, expensive and affects the welfare of these animals, often without a positive result at the end.
We propose here to develop methods and instruments that will allow us and other scientists to use a small insect, the fruit fly, in place of mice to study epilepsy genes. The fruit fly has been of great help in understanding how genes work for over 100 years and 70% of human genes are conserved in this organism.
Studying epilepsy genes in the fruitfly first will allow to study more genes, to study them faster and to identify the most important genes that may be eventually studied in a reduced number of mice. This will beneficial both for patients and for the welfare of the mice.
There are several causes of epilepsy, and scientists are beginning to understand rare forms of epilepsy that are hereditary and are associated with other disorders of sleep and movement. While each single case is rare, altogether hereditary epilepsies are a big portion of the total epileptic population.
Hereditary epilepsies are due to mutation in genes and scientists need to study these genes in small animals to understand how they work and cause epilepsy. This is often done in mice, however studying genes in mice is slow, expensive and affects the welfare of these animals, often without a positive result at the end.
We propose here to develop methods and instruments that will allow us and other scientists to use a small insect, the fruit fly, in place of mice to study epilepsy genes. The fruit fly has been of great help in understanding how genes work for over 100 years and 70% of human genes are conserved in this organism.
Studying epilepsy genes in the fruitfly first will allow to study more genes, to study them faster and to identify the most important genes that may be eventually studied in a reduced number of mice. This will beneficial both for patients and for the welfare of the mice.
Technical Summary
Epilepsy is a debilitating and potentially lethal human condition that affects ~1% of the population. The associated costs of care for patients make it the second neurological condition in terms of burden to the NHS.
Moreover, the epilepsy field is currently being transformed by the impact of genomic studies that are revealing the genetic underpinnings of rare congenital epilepsies often co-morbid with ataxic and sleep disturbances. The large number of candidate loci identified by such studies clearly necessitates the generation of corresponding animal models to confirm the causal connection between mutations in such genes and epileptic seizures. In epilepsy research this almost invariably means rodents.
Drosophila is an ideal organism to test the influence of gene variants on a neurological condition, including polygenic conditions. However, the fly is under-utilized in epilepsy research.
In this application we plan to overcome the obstacles to a full uptake of Drosophila as an alternative and 3Rs-beneficial model for studying epilepsy. Specifically, our scientific aims will be:
1) To develop a methodology for confidently assessing seizures in adult flies. This will include hardware and software development for bioassays to analyse behaviour and neural activation in seizures.
2) To provide proof of principle studies that validate the use of this methodology. This will include analysis of Epg5-Snap25 interactions, of genes linked to Kcna1 and that may ameliorate seizures in Dravet syndrome and generalised epilepsy with febrile seizures, as well as testing ~10 candidate genes identified in human studies by collaborating clinical geneticists.
Through collaboration with project partners and supporting top UK clinical epilepsy genetics, and through a number of pro-active dissemination activities, we aim to facilitate the uptake of flies in epilepsy research, at least to the same level in which they are used in neurodegeneration research.
Moreover, the epilepsy field is currently being transformed by the impact of genomic studies that are revealing the genetic underpinnings of rare congenital epilepsies often co-morbid with ataxic and sleep disturbances. The large number of candidate loci identified by such studies clearly necessitates the generation of corresponding animal models to confirm the causal connection between mutations in such genes and epileptic seizures. In epilepsy research this almost invariably means rodents.
Drosophila is an ideal organism to test the influence of gene variants on a neurological condition, including polygenic conditions. However, the fly is under-utilized in epilepsy research.
In this application we plan to overcome the obstacles to a full uptake of Drosophila as an alternative and 3Rs-beneficial model for studying epilepsy. Specifically, our scientific aims will be:
1) To develop a methodology for confidently assessing seizures in adult flies. This will include hardware and software development for bioassays to analyse behaviour and neural activation in seizures.
2) To provide proof of principle studies that validate the use of this methodology. This will include analysis of Epg5-Snap25 interactions, of genes linked to Kcna1 and that may ameliorate seizures in Dravet syndrome and generalised epilepsy with febrile seizures, as well as testing ~10 candidate genes identified in human studies by collaborating clinical geneticists.
Through collaboration with project partners and supporting top UK clinical epilepsy genetics, and through a number of pro-active dissemination activities, we aim to facilitate the uptake of flies in epilepsy research, at least to the same level in which they are used in neurodegeneration research.