Investigating a novel method of increasing dystrophin production

Dr Malerba’s work aims to boost the production of dystrophin with the ultimate aim of improving dystrophin production in people with Duchenne muscular dystrophy treated with gene therapy.
Dr Malerba’s work aims to boost the production of dystrophin with the ultimate aim of improving dystrophin production in people with Duchenne muscular dystrophy treated with gene therapy.

Background 

Duchenne muscular dystrophy is an incurable condition that destroys skeletal muscles (the muscles that we use to move around) and cardiac muscle (the muscle of the heart). It is caused by a lack of a protein called dystrophin and affects mainly boys and young men. Around 100 boys and, rarely, girls are born each year in the UK with Duchenne muscular dystrophy and most become wheelchair users between the ages of six and 12. 

Gene therapy can restore the production of the missing dystrophin protein in affected children. The current state-of-the-art gene therapy is based on adeno-associated viruses (AAVs), which introduce a shortened version of dystrophin into muscle cells. However, these truncated versions are broken down (degraded) by a process called the unfolded protein response (UPR). All proteins have a three-dimensional structure, which determines how they work. Sometimes the folding of proteins to make three-dimensional structures goes wrong, and the UPR is responsible for the detection and removal of these misfolded proteins. 

What are the aims of the project? 

Using MDUK funding, Dr Malerba aims to assess the capacity of guanabenz acetate, a commercially authorised drug, which targets the UPR, to boost the production of dystrophin and to increase its stability and functionality. Ultimately, this project will determine whether an inhibitor of the UPR can improve the effectiveness of gene therapy and exon skipping approaches in a mouse model of Duchenne muscular dystrophy. 

Why is this research important? 

While this project aims to produce the proof of principle that targeting the UPR is beneficial in mouse models, this would be the first step towards making a drug that could be used in humans.