Steven Sloan, MD, PhD, is an assistant professor in the Department of Human Genetics at the Emory University School of Medicine, as well as a member of the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC). His research focuses on glial development and the role these cells play in neurodevelopmental and neuropsychiatric diseases, including congenital disorders of glycosylation (CDG). Here, he shares his start in rare disease research, exciting discoveries, and future goals.
How and why did you get involved with rare disease research?
I first got involved in rare disease research when I started my laboratory at Emory. Our tools and approaches lend themselves nicely to investigate rare disorders and to better understand their consequences in the brain. We work directly with patient cells and thus can ask questions about how genetic differences manifest in the way the brain develops.
When did you join the FCDGC as an early stage researcher?
I joined the FCDGC in 2020 because we had become particularly interested in studying CDG. This consortium provided both early pilot resources and a rich cohort of expertise to help think about how glycosylation is important in brain development and function.
What were your experiences working with the FCDGC and how has the experience shaped your research career?
Working with the FCDGC has been fantastic. This is truly a leading group of clinical experts and basic science researchers in this group of disorders. Being able to share work with them, collaborate, and develop new ideas has ensured that rare disease work will remain a staple of our laboratory.
Can you share a recent discovery with us, and what it adds to our knowledge of the field?
We are investigating how glycosylation defects in the setting of a disorder called CDG-PMM2 affect brain development. In particular, we are curious if the consequences of this missing enzyme have different effects in different cell types within the brain.
To study this, we used human-induced pluripotent stem cells derived from several patients who have CDG-PMM2. We then differentiated these stem cells into 3D brain organoids, which are a tool we use in the lab to recapitulate brain development in a dish. Since organoids contain various cell types mixed together, we can directly probe which changes occur in which cells specifically.
In our preliminary work, we see that the two most abundant cell types in the brain, neurons and astrocytes, each respond uniquely to missing the PMM2 enzyme. In particular, we think that these cells may be defective in molecules that allow them to physically communicate with each other and migrate to their final destinations within the brain.
Where are you heading next with your research?
We hope to follow up on these preliminary findings by including more patients. Additionally, we hope to test whether drugs that are currently in clinical trials for CDG-PMM2 could reverse some of the findings we see in brain organoids. Beyond that, we hope we might one day develop tools that could allow us to test new drugs or repurposed candidates to help treat these patients.
The Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). FCDGC is funded under grant number U54NS115198 as a collaboration between NCATS, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the Office of Dietary Supplements (ODS).