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Simon Leclerc, MD

Supervisors: Tomoko Takano, Ciriaco Piccirillo
Award: KRESCENT Post-Doctoral Fellowship
Institution: The Research Institute of the McGill University Health Centre
Year: 2021-2024

Study title: Potential roles of antibodies in the pathogenesis of nephrotic syndrome

Dr. Simon Leclerc received his MD from the University of Montreal in 2016 and completed his internal medicine (2019) and nephrology (2021) training at the same university, spending most of his rotations at Hôpital Maisonneuve-Rosemont in Montreal. He is currently pursuing his PhD in Experimental Medicine at McGill University under the supervision of Dr Tomoko Takano and Dr Ciriaco A. Piccirillo. His project is centered around a novel mouse model of minimal change disease, one of the most common forms of nephrotic syndrome for which there is no definitive cure. This new mouse model involves autoantibodies directed against an important podocyte protein. Dr Leclerc hopes that studying this model will help to better understand minimal change disease and, maybe, open new therapeutic possibilities.

Lay Summary
Nephrotic syndrome (NS) is a common form of kidney disease that happens when the kidney leaks a massive quantity of protein in the urine. This continuous loss of protein creates body swelling and is toxic to the kidney. Untreated, it leads to chronic kidney disease and dialysis. Minimal change disease (MCD) is a frequent cause of NS. It represents 90% of cases in children and 10% in adults. Steroids are the first line therapy for MCD. However, they are not always effective and relapses are frequent after successful treatment. They also have serious side effects: growth retardation, weight gain, weak bones and depression. Recently, a promising medication reducing the production of antibodies, rituximab, is gradually being used with success as a personalized treatment for MCD. The fact that this medication is effective makes us think that antibodies directed against kidney cells might cause MCD. However, this is not proven yet because the mechanisms leading to MCD are still unknown after five decades of research. This slow progress is in great part due to the lack of an animal model copying the human disease. Developing a more realistic model is crucial to better understand MCD and develop personalized treatments. Procedure and outcomes: In order to achieve this goal, we have 3 principal aims: 1) In collaboration with Dr. Yan of Kyorin University in Japan, our team is developing a mouse that have antibodies directed against an important protein in the kidney cells, Crb2. These mice develop a disease similar to MCD. We will study the characteristics of their kidney disease and compare it to human MCD. We expect that this model will resemble human MCD, allowing us to study its mechanisms. 2) Under the microscope, we will expose kidney cells to the antibodies against Crb2. We will then analyze what effect this antibody have on kidney cells by different state-of-the-art techniques. We expect finding lesions on our cells that are similar to those on the kidney cells of patients with MCD. 3) We will develop a test to measure the blood levels of the antibody against Crb2. We will then use this test to explore the presence of this antibody in human patients with MCD and other forms of NS. The patients selected are already participating in two long term studies about NS in Quebec. We think that we might find the antibodies against Crb2 in human patients. Relevance to patients: Our project will hopefully allow us to have a better understanding of MCD. Most importantly, if we find that the antibody against Crb2 is present in human patients, it could allow us to develop a treatment against that antibody. A personalized treatment like this would greatly improve the life of patients with MCD by allowing them to achieve long-term remission with less side effects.

Legend and glossary:
NS = Nephrotic Syndrome
MCD = Minimal Change Disease.