Mitochondrial DNA depletion syndrome: developing a new treatment

Research Training Fellowship*: Dr Nandaki Keshavan

Mitochondrial DNA depletion syndromes (MDDS) are rare and severe genetic disorders that affect an estimated one in every 22,000 children in the UK.¹ In its most severe form, the condition starts in early infancy and has devastating symptoms, causing a variety of neurological problems and progressive liver failure – and tragically, many children will not live to see their second birthday. Dr Nandaki Keshavan at UCL Great Ormond Street Institute of Child Health in London is aiming to develop a new gene therapy for children with MDDS. Although his research is still at an early stage, it provides hope for a future new treatment that would transform the lives of children with this incurable condition.

How are children’s lives affected now?

Mitochondria are the powerhouses of our cells, performing the essential job of generating energy. If certain genes that are involved in making the mitochondria’s own DNA are faulty, this affects the energy supply. That can have disastrous consequences for organs that need lots of energy, such as the brain and the liver.

Around one in five children with MDDS have a severe type that is caused by faults in a gene called DGUOK.² They will experience progressive liver disease and neurological symptoms, including seizures and developmental delay.

“A liver transplant can help save some children from liver failure but unfortunately, it does not improve or prevent their brain disease,” says Dr Keshavan. “Sadly, there is no cure for MDDS and most children will ultimately lose their lives – often at a very young age.”

“There is an urgent need to find effective new treatments, which would give hope to children and their families who are affected by this heartbreaking condition,” he adds.

How could this research help?

“Our goal is to use gene therapy to cure children with a severe form of MDDS,” says Dr Keshavan.

The team is planning to use specially designed carriers to deliver a correct copy of the DGUOK gene into liver and brain cells in a laboratory model.

“The use of gene therapies to treat other rare disorders is showing promise but this approach has not yet been used for treating DGUOK deficiency,” says Dr Keshavan.

The team will work out the best way to maximise delivery of the correct copy of the DGUOK gene to liver and brain cells and assess its effectiveness.

“We hope that gene therapy will slow down or stop the progression of the disease, laying the foundations for future clinical trials in patients,” says Dr Keshavan.

If their approach works, the researchers hope to develop similar treatments for children with other forms of MDDS, and for other mitochondrial disorders, helping more children with these devastating conditions.

References

1. UK Genetic Testing Network Steering Group, September 2013: http://bit.ly/2HUGYWR
2. Sezer, T et al. Novel deoxyguanosine kinase gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome Journal of Childhood Neurology. 2015; 30(1): 124-28.

* Research Training Fellowships:

Each year, Action Medical Research awards these prestigious grants to help develop some of the UK’s brightest doctors and scientists as future leaders in children’s research.