Title: Gene therapy for mitochondrial DNA depletion syndrome
Funder: Action Medical Research

Abstract: Background_x000D_ Mitochondria are tiny structures within cells that provide the energy needed for most of a cell's activities. Mitochondria contain their own DNA that codes for some of the key proteins required for normal mitochondrial function. Mitochondrial DNA depletion syndrome (MDDS) is a rare and severe form of mitochondrial disease which affects an estimated one in every 22,000 children in the UK. Around one in five cases of MDDS is caused by mutations in a gene called DGUOK. This gene is essential for the formation of nucleotides (the building blocks of DNA) and mutations in DGUOK lead to reduced mitochondrial DNA formation. In its most severe form, this condition appears in early infancy and has devastating effects on the brain and liver. Affected children experience neurological symptoms including seizures and developmental delay, combined with progressive liver failure, and sadly, often do not survive beyond their second birthday. There are no effective treatments. Liver transplantation has saved some children from liver disease, but has not been able to improve or prevent disease within the brain. There is therefore an urgent need to find new effective treatments._x000D_ _x000D_ The research project _x000D_ These researchers aim to develop a cure for MDDS using a gene therapy approach. Using a viral vector, they will deliver a correct copy of the DGUOK gene to a mouse model of MDDS. Viral vectors are modified to be rendered harmless and used as a way of transporting genes into target cells. The team will investigate the best dose, administration route and timing of treatment to maximise beneficial effects. If this study shows that mitochondrial gene therapy is an effective form of treatment, it will lay the foundation for future clinical trials in patients and take us one step closer to finding a cure for MDDS. In the future, the researchers expect to broaden their use of gene therapy to other genetic causes of MDDS and to mitochondrial diseases in general, to help a larger number of children with these devastating diseases. _x000D_

Lay abstract: Background_x000D_ Mitochondria are tiny structures within cells that provide the energy needed for most of a cell's activities. Mitochondria contain their own DNA that codes for some of the key proteins required for normal mitochondrial function. Mitochondrial DNA depletion syndrome (MDDS) is a rare and severe form of mitochondrial disease which affects an estimated one in every 22,000 children in the UK. Around one in five cases of MDDS is caused by mutations in a gene called DGUOK. This gene is essential for the formation of nucleotides (the building blocks of DNA) and mutations in DGUOK lead to reduced mitochondrial DNA formation. In its most severe form, this condition appears in early infancy and has devastating effects on the brain and liver. Affected children experience neurological symptoms including seizures and developmental delay, combined with progressive liver failure, and sadly, often do not survive beyond their second birthday. There are no effective treatments. Liver transplantation has saved some children from liver disease, but has not been able to improve or prevent disease within the brain. There is therefore an urgent need to find new effective treatments._x000D_ _x000D_ The research project _x000D_ These researchers aim to develop a cure for MDDS using a gene therapy approach. Using a viral vector, they will deliver a correct copy of the DGUOK gene to a mouse model of MDDS. Viral vectors are modified to be rendered harmless and used as a way of transporting genes into target cells. The team will investigate the best dose, administration route and timing of treatment to maximise beneficial effects. If this study shows that mitochondrial gene therapy is an effective form of treatment, it will lay the foundation for future clinical trials in patients and take us one step closer to finding a cure for MDDS. In the future, the researchers expect to broaden their use of gene therapy to other genetic causes of MDDS and to mitochondrial diseases in general, to help a larger number of children with these devastating diseases. _x000D_

Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CONGENITAL DISORDERS