The high risk of neuropsychiatric syndromes in DMD patients warrants early intervention to achieve the best possible quality of life. We have entered an unprecedented era in DMD research with new drugs entering the market that can restore dystrophin expression in the muscle. Unravelling the function and pathophysiological significance of dystrophin in the brain has therefore become a high research priority. Unlike muscle, the central nervous system sees the expression of a large variety of DMD transcripts implicated in diverse cellular processes. The most predominant in the brain is Dp71; distal DMD mutations affecting its expression are linked to cognitive impairment. Dp71 is alternatively spliced producing several sub-isoforms with different subcellular localisations. For example, Dp71d (including exon 78) is expressed in the nucleus whilst Dp71f (lacking exon 78) is expressed in the cytoplasm. Thus, RNA processing critically regulates the localisation and function of dystrophin in the brain. Yet we understand very little about how DMD is regulated in this way. This knowledge gap is critical given that RNA-based brain-targeting treatments for Duchenne are already in early clinical development. Our objective is to fill this knowledge gap and inform drug development in this area.
Duchenne muscular dystrophy is a fatal childhood genetic disorder. It is caused by the body-wide absence of a muscle protein called dystrophin. Alongside muscle symptoms; the loss of dystrophin in the brain leads to intellectual disability and conditions like autism. But what does a muscle protein do in the brain? We understand very little about how dystrophin is made in the brain and what it does there. Our project will use cell models of the nervous system as well as patient cells and data to fill this urgent gap in knowledge. To achieve the best possible quality of life we need to tackle every element of Duchenne. This project will inform the development of effective brain-targeting treatments.