Title: A translational approach to neurodevelopmental disorders associated with defective autophagy
Funder: Action Medical Research

Abstract: Background_x000D_ There are many genetic neurodevelopmental disorders affecting children. They are typically characterised by progressive loss of speech, vision, hearing and movement and frequently associated with seizures and severe learning difficulties. Sadly, for most of these conditions, there is no cure or effective treatment and many prove fatal during early childhood. Although individually rare, these disorders often have similar underlying mechanisms and by investigating such pathways, it may be possible to understand and identify potential treatments for a wide range of different neurodegenerative conditions. These researchers are particularly interested in a process called autophagy. Autophagy is an important intracellular 'quality control' process that removes unwanted proteins and structures which interfere with normal cell function and development. Defective autophagy has been implicated in the development of adult-onset neurodegenerative disorders such as dementia. More recently, autophagy defects have emerged as a common cause of a number of early-onset neurodevelopmental conditions affecting children. The team plans to study three different childhood disorders to identify precisely the faulty steps associated with defective autophagy. _x000D_ _x000D_ The research project_x000D_ The researchers will use fruit flies (Drosophila) to investigate the genetics of a disorder called Vici syndrome and two other neurodevelopmental disorders with defective autophagy. Once they have established a clear picture of how the faulty genes affect autophagy, they will then see if the process can be corrected using either drugs or gene therapy. These potential treatments will first be tested in the existing fly model and if successful, the team will then carry out similar tests in cells from patients. This part of the project will involve stem cell technology where skin cells from patients are used to create stem cells (unspecialised cells which have the ability to develop into many different types of cells). By changing these stem cells into nerve cells (still carrying the relevant faulty genes), the team will create a patient cell model in which they can test the findings already obtained in the fly model. Their aim is to identify and validate gene therapy and drug development targets for a range of autophagy-related disorders. By acting on shared pathways, these treatments could benefit a group of childhood neurological conditions, rather than just one single rare disorder. It is likely that the models and techniques developed in this project will be a valuable resource in future studies to evaluate treatments for a wide range of neurological disorders such as ataxia and early-onset dementia._x000D_ _x000D_

Lay abstract: Background_x000D_ There are many genetic neurodevelopmental disorders affecting children. They are typically characterised by progressive loss of speech, vision, hearing and movement and frequently associated with seizures and severe learning difficulties. Sadly, for most of these conditions, there is no cure or effective treatment and many prove fatal during early childhood. Although individually rare, these disorders often have similar underlying mechanisms and by investigating such pathways, it may be possible to understand and identify potential treatments for a wide range of different neurodegenerative conditions. These researchers are particularly interested in a process called autophagy. Autophagy is an important intracellular 'quality control' process that removes unwanted proteins and structures which interfere with normal cell function and development. Defective autophagy has been implicated in the development of adult-onset neurodegenerative disorders such as dementia. More recently, autophagy defects have emerged as a common cause of a number of early-onset neurodevelopmental conditions affecting children. The team plans to study three different childhood disorders to identify precisely the faulty steps associated with defective autophagy. _x000D_ _x000D_ The research project_x000D_ The researchers will use fruit flies (Drosophila) to investigate the genetics of a disorder called Vici syndrome and two other neurodevelopmental disorders with defective autophagy. Once they have established a clear picture of how the faulty genes affect autophagy, they will then see if the process can be corrected using either drugs or gene therapy. These potential treatments will first be tested in the existing fly model and if successful, the team will then carry out similar tests in cells from patients. This part of the project will involve stem cell technology where skin cells from patients are used to create stem cells (unspecialised cells which have the ability to develop into many different types of cells). By changing these stem cells into nerve cells (still carrying the relevant faulty genes), the team will create a patient cell model in which they can test the findings already obtained in the fly model. Their aim is to identify and validate gene therapy and drug development targets for a range of autophagy-related disorders. By acting on shared pathways, these treatments could benefit a group of childhood neurological conditions, rather than just one single rare disorder. It is likely that the models and techniques developed in this project will be a valuable resource in future studies to evaluate treatments for a wide range of neurological disorders such as ataxia and early-onset dementia._x000D_ _x000D_

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL