The Kidney Foundation of Canada

Dr. Alessia Fornoni 

Dr. Alessia Fornoni

University of Miami, Florida

Targeting podocyte lipotoxicity in Alport Syndrome


2017-2018:  $100,000  |  Alport Syndrome Foundation Grant  |  Category: Alport Syndrome

Biography

Dr. Fornoni is tenured Professor of Medicine and Molecular and Cellular Pharmacology at the University of Miami Miller School of Medicine. She is the Chief of the Division of Nephrology and Hypertension and serves as and Director and Chair of the Peggy and Harold Katz Drug Discovery Center. She is also the Associate Director of the MD PhD program. In the year 2013, Dr. Fornoni gained experience in drug development as Global Head of Discovery in Cardiovascular and Metabolism at Hoffman-La Roche in Basel. She is currently the Vice-President and Chief Scientific Officer of L&F Health LLC, a small start up company focused on finding a cure for patients affected by chronic kidney diseases.

As a physician-scientist who has maintained a resolutely focused research program that has provided novel and seminal contributions to our understanding of the pathogenesis of kidney disease, her research has been supported by grants from National Institutes of Health, industry and private foundations. She has received prestigious awards, she is a member of ASCI, she serves on the editorial board of Diabetes and Kidney International, she was visiting professor at more than 50 academic institutions and international meetings worldwide. She serves as grant reviewer for NIH, DOD, ADA, AHA, UK-diabetes and the Italian Ministry of Health. Her contributions have been published in high impact journals: Journal of Clinical Investigation, NEJM, Nature Medicine, Science Translational Medicine, Journal of Biological Chemistry, Diabetes among others. She successfully trained several graduate students and post-doctoral fellows, further supporting her accomplishments, dedication and perseverance, and more importantly her unstinted commitment as a physician-scientist.

Moving forward, her vision is one that brings industry, investors and not for profit organizations around the table with the intent to match science with innovation and patients’ motivation to find a cure for kidney diseases.

Lay Summary

Alport Syndrome (AS) is a hereditary disease of glomerular basement membranes
(GBM) linked to mutations in genes coding for different chains of collagen type IV.
Although the GBM is primarily composed of laminin and Collagen type IV, the de novo
production of the α1 chain of collagen type I (Col I) has been observed in experimental
models of AS.

Discoidin domain receptor 1 (DDR1) is a unique receptor tyrosine kinase that is
activated by extracellular matrix but that can also be activated by collagen. DDR1 deletion
in Col4a3 knockout (KO) mice, a mouse model for AS, improves survival and renal
function. Podocytes and their proper interaction with the GBM are crucial to maintain the
permeability of the glomerular filtration barrier. Our in vitro and in vivo preliminary data
indicate that DDR1 can be activated by collagen I in human podocytes. Furthermore, we
demonstrate that Col I-induced or genetic activation of DDR1 causes cellular lipotoxicity,
a phenomenon that we recently demonstrated to be a key determinant of podocyte injury
in other glomerular diseases. In particular, we show that the uptake of free fatty acids
(FFAs) is increased in Col I treated podocytes and requires the activation of DDR1 which
will ultimately lead to intracellular lipid accumulation due to increased fatty acid (FA)
uptake. This phenomenon is also reflected in Col4a3 KO mice, where increased DDR1
activity in kidney cortexes correlates with blood urine nitrogen (BUN) and is associated
with increased lipid deposition and increased expression of scavenger receptor B,
cluster of differentiation 36 (CD36), a protein involved in FA uptake, cholesterol
absorption and activation of inflammatory pathways. Studies by others have shown that
CD36 activation can be blocked by the clinically available compound Ezetimibe.

The goal of this proposal is to demonstrate a novel mechanism of podocyte
lipotoxicity in AS that is amenable to therapeutic intervention through a repurposing
strategy of Ezetimibe.

We will test the novel hypothesis that DDR1-induced podocyte injury in AS
requires CD36 dependent fatty acid and cholesterol uptake and that inhibition of
CD36-dependent lipotoxicity with Ezetimibe can prevent the progression of kidney
disease in Alport Syndrome.

We will address this hypothesis using a combined in vitro and in vivo approach to
investigate the role of DDR1 in lipid induced podocyte damage and to determine if CD36
inhibition can prevent intracellular lipid accumulation and podocyte injury in Col4a3 KO
mice.

If our hypothesis is confirmed, repurposing strategies for the use of Ezetimibe to
treat patients with AS should be fast and safe, as Ezetimibe is an already FDA-approved
drug currently labeled for the treatment of patients with hypercholesterolemia.