We’re proud to help fund the first Zebrafish models of CLOVES

We’re pleased to announce a $100,000 research donation to the University of Edinburgh – Patton Lab – to develop zebrafish models of CLOVES.   

Dr. Hannah Brunsdon has written a lay summary about this project below.

“People with CLOVES syndrome commonly have fatty growths, abnormal formation of blood vessels and lymphatics, dark skin lesions, and alterations in growth of some bones, among other problems. These changes are detectable from birth and often progress, causing increasing health problems during childhood and beyond. CLOVES syndrome is caused by changes that arise spontaneously in the very earliest stages of life. These affect the PIK3CA gene, causing it to become hyperactive. This causes increases in growth signals in affected tissues, leading to patchy, poorly controlled growth of cells carrying the PIK3CA mutation.

Laboratory studies of cells or animals carrying the CLOVES mutations in PIK3CA have already increased our understanding of the development of CLOVES syndrome, and are helping to guide new treatment strategies. However, CLOVES syndrome is unusually complex to mimic for these studies, because there is a mixture of healthy and PIK3CA-altered cells in affected people, the gene changes arise randomly after conception instead of being inherited, and changes can occur in a wide variety of different cells and tissues. This is why CLOVES syndrome shows itself very differently from person to person.

In this project, we aim to develop zebrafish as a new, clinically relevant animal model of CLOVES syndrome. Despite differences in their appearance to us, zebrafish are well established as models for human disease, with at least 70% of human disease-causing genes having zebrafish counterparts. Zebrafish breed rapidly, their genes can readily be altered, and development of key internal tissues and organs can be observed directly from the first cell divisions to adulthood. This means that, uniquely, events occurring during CLOVES syndrome development in a fish can be followed at the cellular level, in real time.

We plan to ‘edit’ zebrafish Pik3ca using CRISPR-Cas9 technology to introduce the main CLOVES syndrome mutation alongside the normal gene. We will use fluorescent markers to watch the behaviour of Pik3ca-mutant cells and their interactions with surrounding normal cells. In this way, we will be able to capture the earliest events that cause clinical problems in people, and watch the onset and progression of CLOVES syndrome in a living intact animal, investigating whether there is a critical developmental time window for developing CLOVES. We believe this approach will allow us to model CLOVES syndrome at a higher resolution than possible in other animal models so far, and provides a stepping stone to using this model to screen for new therapies to treat CLOVES syndrome.”

Thank you to our donors for making this research investment happen!