Program Directors
 

Award: KRESCENT Post-Doctoral Fellowship
Supervisor(s):  William Stanford
Institution: Ottawa Hospital Research Institute
Year: 2024-2027

Study title:  Mechanism of tuberous sclerosis complex (TSC) kidney disease pathogenesis

Biography

Dr. Adrianna Douvris completed her M.D. at the University of Toronto, and Internal Medicine and Nephrology residencies at the University of Ottawa. She is completing her PhD as part of the Clinician Investigator Program in Ottawa under the supervision of Dr. Kevin Burns, studying microRNA therapy in acute kidney injury. Next, she will begin her post-doctoral fellowship under the supervision of Dr. William Stanford at the Ottawa Hospital Research Institute. Her KRESCENT post-doctoral fellowship will focus on tuberous sclerosis complex (TSC) kidney disease, a genetic form of kidney disease, using novel models known as kidney organoids (‘mini-kidneys’). She hopes that these models will improve our understanding of TSC kidney disease and lead to new treatment discoveries.

Lay Summary
Background: Chronic kidney disease affects up to 13% of the population globally yet curative treatments are unavailable. Genetic contributors to chronic kidney disease are being increasingly recognized. Tuberous sclerosis complex (TSC) is a genetic disorder that affects an estimated 1/6000-1/10000 people and results in the development of benign tumors in many organs in the body.  The root cause of TSC is due to changes in TSC genes (TSC1 or TSC2). These changes lead cells to grow and divide uncontrollably, causing benign tumors. Importantly, approximately 4/5 patients with TSC have kidney disease, which is often progressive, and also results in the development of benign tumors called renal angiomyolipomas (R-AML) and kidney cysts. R-AMLs can also contribute to chronic kidney disease progression by growing into normal kidney tissue or by bleeding. Studying how kidney disease develops in people with TSC has been limited by imperfect experimental models. Also, current therapy is not curative and, for some patients, is ineffective.
 
Purpose: Dr. Stanford ‘s laboratory has developed ‘mini-kidneys’ from human stem cells, known as kidney organoids, to model TSC kidney disease. These mini-kidneys provide a more realistic experimental model compared to traditional cells in a dish. Further, these mini-kidneys can be injected into mouse kidneys, overcoming some limitations of mini-kidneys and allowing for the study of human TSC disease in a mouse model.  This model is called a xenograft.  I want to use these novel models to understand how kidney disease develops in TSC and to test new therapies. Since TSC disease can vary between patients, I also want to generate ‘mini-kidneys’ and xenografts from patient kidney samples and compare them to the stem-cell derived models.
 
Method: I will generate kidney organoids and xenografts of TSC kidney disease from human stem cells without the genes TSC1 or TSC2 to study how the disease develops, and to test medications. In Aim 1, I will determine how individual cell types taken from a mini-kidney without TSC1 or TSC2 contribute to the development of TSC kidney disease.  In Aim 2, I will use these models to test promising drug candidates that are either already clinically approved or in Phase 1 clinical trials for other medical disorders. In Aim 3, I will generate kidney organoids and xenografts from surgical kidney specimens from people with TSC to compare them with our human stem cell-derived models using a cutting-edge technology called ‘spatial transcriptomics’ that will give us detailed information on gene activity at the single-cell level. 
 
Anticipated Outcomes: These studies will increase our understanding of the mechanisms contributing to kidney disease development in TSC and will identify promising new therapies for people suffering from TSC kidney disease.
 
Patient Engagement: Our research study will utilize kidney tissue from patients with TSC kidney disease. I have opportunities to engage patients in research discussions through my clinical work. I will also present our research and engage in discussions with members of the public including patients and their families at local community engagement events.
 
Relevance to patients/community: 4 out of 5 people with TSC have kidney disease. This includes benign tumors, cysts, and chronic kidney disease. Yet, our understanding of how kidney disease develops in TSC and current therapies are limited. Human stem cell-derived kidney organoid and xenograft models are promising tools to better understand TSC kidney disease and provide an opportunity to accelerate treatment discoveries. Finally, these models have the potential to improve research progress for other causes of chronic kidney disease which would have a future positive impact for more people living with kidney disease.
 
Conclusion: Dr. Stanford’s laboratory has successfully generated kidney organoid and mouse xenograft models of TSC kidney disease. We believe that the proposed studies will improve our understanding of TSC kidney disease. We are optimistic that testing candidate drugs in organoid and xenograft models will identify promising therapies for a TSC kidney disease clinical trial. Overall, our primary goal is to improve the lives of people living with TSC-related kidney disease.