Project Hypothesis and Goals: the fruitfly Drosophila melanogaster is a suitable animal to study Dravet syndrome

• This insect has a gene equivalent to the human SCN1A gene. Mutations in this gene cause seizures, and these mutants respond to anticonvulsant drugs used in patients.
• In Drosophila melanogaster we can use genetic modification techniques more sophisticated than those available for current models (mainly mice and cell culture)
• Our goal is to generate genetically manipulated flies to represent clinical mutations to understand the underlying disease mechanism and address clinical issues such as the diverse clinical picture, and the lack of therapeutic solutions.

Aims

• We will eliminate the function of para (the fly equivalent to SCN1A), leaving a landing site for human SCN1A with selected clinical mutations. This aim is already completed.
• We will introduce the mutant human SCN1A genes over the inactivated fly gene. We will create a fly strain for each mutation. This aim is under way.
• Analysis of the models. Once we have generated these models in the fly, we will use them to study the effect of the mutations on the nervous system and to understand the differences between patients, and in the long term use the to find effective treatments. This aim requires additional funding.

Deliverables

• An understanding of the effect of the different clinical mutations on the physiology and function of the neurons.
• A novel platform to investigate disease mechanisms, and to find therapeutic solutions.

Impact and Innovation

Current models to understand Dravet syndrome are mostly based on complete elimination of the gene function in mutant mice or overexpression of mutations in cultured cells and do not represent the clinical diversity of the disease. Our models, based on the same mutations found in patients and expressed in physiological conditions in whole animals, are a novel approach complementary to the current models.

Cost until December 2019 covered
Cost until December 2020: 30,000 €