A normal glomerulus (left) and an enlarged fibrotic glomeruli (right).

Accelerating the Discovery of Anti-Fibrotic Therapies for Chronic Kidney Disease

By Alexa Desimone

Fibrotic disorders are becoming increasingly prevalent; they take many forms and are often life threatening. It is estimated that fibrosis accounts for almost half the chronic diseases afflicting industrialised countries.1 Chronic kidney disease (CKD) is one of the most devastating and common examples of fibrotic disease.2,3 In the kidney , fibrosis is characterized by the accumulation of extracellular matrix proteins, typically in the glomerulus and tubulointerstitium, which inevitably infringes on nearby structures, resulting in hypoxia, tubular atrophy, and inflammatory cell infiltration.4 With time, the formation of fibrotic lesions leads to irreversible end-stage kidney failure. Unfortunately, four million Canadians are currently living with CKD, with the majority requiring dialysis or kidney transplantation5. Despite its prevalence, therapeutic strategies targeting profibrotic mechanisms in CKD are lacking.

Dr. Richard E. Gilbert, an endocrinologist at St. Michael’s Hospital in Toronto, has dedicated his professional career to identifying therapeutic strategies for the prevention and treatment of chronic fibrotic disorders, focussing predominantly on CKD and heart failure. He is particularly interested in these disorders in the diabetic setting given that diabetes is present in approximately 30-50% of all patients with either heart failure or CKD. Dr. Gilbert is a Tier 1 Canada Research Chair in Diabetes Complications, Professor of Medicine at the University of Toronto, and Head of the Division of Endocrinology at St. Michael’s Hospital/Unity Health Toronto.

St. Michael's Hospital

Richard E. Gilbert
MD, FRCPC, FRACP, FACP, FASN, PhD
Professor of Medicine, University of Toronto
Head of the Division of Endocrinology, St. Michael’s Hospital
Canadian Research Chair in Diabetes Complications

Growing up in Adelaide, a small city in South Australia, Dr. Gilbert completed his medical training at Flinders University. Excited by the prospect of continuing in clinical medicine while also pursuing his research interests, he accepted an offer as a one-year lecturer at London University in London, England. As Dr. Gilbert described, “The salary was barely enough to live on but the opportunity it afforded me in the academic, social and societal spheres was immeasurable”. This was a pivotal moment in Dr. Gilbert’s career. Rather than staying on a predictable and linear path, he made a bold choice that would enrich his academic and life experiences.

Returning to Australia, he completed his medical fellowship and doctoral studies in the clinical and molecular aspects of diabetic kidney disease and established a highly productive research laboratory at St. Vincent’s Hospital in Melbourne, Australia. But it was time for Dr. Gilbert to broaden his horizons once again by seeking to do a sabbatical in Toronto where his wife, Susan, was from. Rather than offers for his intended sabbatical, Dr. Gilbert was invited to apply for newly available clinician-scientist positions at two University of Toronto institutions. “Coming to a city with such great research, collegiality, and collaboration made the decision easy” said Dr. Gilbert. So, in 2006 he set up his laboratory and took up his post at St. Michael’s Hospital as a clinician-scientist.

image provided by Dr. Gilbert

A normal glomerulus (left) and an enlarged fibrotic glomeruli (right). source: “Zhang Y, Connelly KA, Thai K, Wu X, Kapus A, Kepecs D, Gilbert RE. Sirtuin 1 Activation Reduces Transforming Growth Factor-β1–Induced Fibrogenesis and Affords Organ Protection in a Model of Progressive, Experimental Kidney and Associated Cardiac Disease. The American journal of pathology. 2017 Jan 1;187(1):80-90.”

The pathogenesis of diabetic kidney and heart disease, encompassing both glucose-dependent and glucose-independent pathways, requires a multifaceted approach to establish therapeutic strategies.6 In the kidney, fibrosis impairs filtration and tubular cell function, whereas in the heart, it impairs both systolic and diastolic function with stiffening and impaired contractility of the left ventricle.7 While investigating the pathogenesis of fibrosis is of great interest to Dr. Gilbert, his real desire was to develop new therapies that could be used to treat patients. With this in mind, he co-founded a biotechnology company called Fibrotech Therapeutics which attracted NIH funding to progress its lead compound, FT011, into early human studies. In pre-clinical studies, FT011 has demonstrated anti-fibrotic and anti-inflammatory properties that have shown to be useful in treating chronic heart failure associated with diabetic kidney disease.8 After Fibrotech was sold to Shire, a large, multi-national pharmaceutical company, Dr. Gilbert, believing that a single drug was unlikely to cure a complex disease process such as fibrosis, continued to investigate novel approaches to combat fibrotic disease.

In 2016, Dr. Gilbert along with three other co-principal investigators were awarded a $1-million Transformational Diabetes Team Research Grant from the University of Toronto’s Banting and Best Diabetes Centre. This funding was used as the foundation for another endeavor to develop new anti-fibrotic therapies. Along with funding from MaRS Innovation and an investment from another biotechnology company, Evotech, Fibrocor Therapeutics began utilizing archival kidney biopsy tissue to uncover transcriptomic changes that are linked to fibrosis. One of the very first analyses of the data uncovered the discoidin domain receptors (DDRs), unique tyrosine kinase receptors that signal in response to non-diffusible collagens and have been shown to be upregulated in fibrotic diseases.9 Their team identified DDRs as a close correlate of declining kidney function and the extent of fibrosis. With the help of Evotech, Fibrocor’s drug development partner, they hope to develop inhibitors of DDR to treat, prevent, and possibly reverse fibrotic disease.

Dr. Gilbert embodies the concept of bench-to-bedside medicine in its truest sense. With a strong background in basic research, he knew that his findings could benefit innumerable patients with CKD. He took it upon himself to try and turn his discoveries into therapeutic agents that help patients. “It’s possible to be a dedicated academic and devoted clinician, but to also be cognisant of the need to engage with industry and the business community in order to progress your ideas towards the clinic”, says Dr. Gilbert. He hopes to inspire young clinician-scientists to always look for opportunities that enrich your life experience as well as your professional life.

References:
1. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117(3):524-529.
2. Hewitson TD. Fibrosis in the kidney: is a problem shared a problem halved? Fibrogenesis Tissue Repair, 2012;5, S1:S14.
3. Canadian Institute for Health Research. Annual Statistics on Organ Replacement in Canada Dialysis, Transplantation and Donation, 2008 to 2017. CIHI Snapshot, December 2018. Available from:https://secure.cihi.ca/free_products/snapshot-corr-2018-en.pdf.
4. Gilbert RE, Zhang Y, Williams SJ, et al. A purpose-synthesised anti-fibrotic agent attenuates experimental kidney disease in the rat. PLoS One, 2012:7(10), e47160.