Stuart Cobb

Dr Stuart Cobb is a Simons Fellow and Reader in Neuroscience at the Patrick Wild Centre and Centre for Discovery Brain Sciences, University of Edinburgh.

Abnormalities in brain development, once thought to be irreversible in adults, are assumed to underlie a range of autism, intellectual disability and epilepsy disorders. There is growing evidence that reversing the underlying molecular deficits can result in substantial improvements in function and this knowledge is in turn changing the way we view and envisage treating such disorders in the future.

The aim of my laboratory is to understand the tractability of neurodevelopmental disorders (NDDs) to therapeutic intervention. This includes gaining an understanding of those aspects of NDDs that genuinely result from aberrant early brain development to features that result from ongoing dysfunction within the mature nervous system. This is important not only for a fundamental understanding of the pathophysiology but also in terms of windows of opportunity for treatment.

A major focus of our efforts is to develop gene therapy for Rett syndrome and related disorders. My laboratory was the first to report the ameliorative effect of gene therapy in mice modelling the disorder and work going forward aims to optimize gene therapy cassettes for efficacy and safety.

Strategy taken to test the reversibility and then correct neurodevelopmental disorders. A. Example of progressive increase in neurological severity in a mouse model of Rett syndrome before and following switching back on the Mecp2 gene. B. Having established reversibility, the gene can be packaged in a virus along with appropriate regulatory elements to infect brain cells. C. It is considered important to deliver and achieve physiological levels of the gene product (protein) in the appropriate cell types in the brain. This is especially challenging in x-linked neurodevelopmental disorders where there is often mosaic distribution of cells expressing the aberrant protein. In these instances, it may be desirable to selectively target those affected cells.

In addition to classical gene augmentation therapy, we are exploring RNA and splicing-based approaches to bypass disease-causing mutations in neurodevelopmental disorders. These approaches have the advantage that they would correct the root cause of the disorder in a cell appropriate manner and have added safety benefits such as not risking overexpression issues.

Whilst the focus of the laboratory is presently on monogenic disorders at the more severe end of the NDD scale, it is hoped our work will provide a platform for future efforts in other NDDs. By extending our approach, we expect our strategy will allow us to predict, and ultimately test, which NDDs or particular phenotypes in NDD are most amenable to correction. Our work feeds into the wider goal of the Patrick Wild Centre which is to identify common or convergent underlying mechanisms of dysfunction in NDDs.

Email: stuart.cobb@ed.ac.uk