New translational collaboration aims to transform approach to heart muscle disease

Source: Faculty of Medicine Alumni and Friends

To truly personalize medicine, you need to model the disease of individual patients realistically in 3D. That is exactly what molecular pharmacologist Terry Hébert and heart failure specialist Nadia Giannetti, MDCM’91, will be doing in a new, cutting-edge “heart-in-a-dish” project aimed at personalizing and dramatically improving the prevention, understanding and treatment of cardiomyopathy over the next decade.

Using stem cells derived from blood samples donated by 100 cardiomyopathy patients at the McGill University Health Centre (MUHC), they will develop miniature, 3D beating hearts as pre-clinical models that resemble human hearts in their physiological and cellular activity, and replicate the distinct features of heart muscle disease of individual patients in the real world. These miniature hearts, also known as organoids, will include self-organizing heart muscle cells, endothelial cells, fibroblasts, and vascular smooth muscle cells.

“These personalized, mini-heart models will allow us to better understand the different disease mechanisms and causes of cardiomyopathy in individual patients, develop predictive biomarkers to detect disease before symptoms occur, and test whether particular drugs or drug combinations might work better in specific patients,” says Hébert, a professor in the Department of Pharmacology and Therapeutics and Assistant Dean, Biomedical Science Education.

“We’re also creating a unique, patient-based drug discovery platform that can help us to design and develop personalized targeted therapies to modify or reverse the disease, rather than just treat symptoms,” explains Hébert, who uses innovative biosensors in his work.

The heart-in-a-dish project, which is part of the larger McGill Cardiomyopathy Initiative, is supported by a $3-million donation from the Courtois Foundation to the McGill Faculty of Medicine to fund five years of research in Hébert and Giannetti’s labs to better understand and treat cardiomyopathy using patient-derived stem cell and organoid models.

It also complements the Courtois Cardiovascular Signature Study, a 10-year research project co-led by Giannetti at the MUHC’s Glen campus that’s collecting biological materials, MRI imaging and clinical data from participants, and seeks to understand all the factors that contribute to heart disease using artificial intelligence to puzzle out previously undetected patterns.

Cardiomyopathy is a disease of the heart muscle, which can lead to heart failure, irregular heart rhythms, blood clots or sudden death. Heart failure is the leading cause of hospitalization for people over 65 in North America, but it can affect people of all ages. About 600,000 Canadians are living with the condition and the five-year survival rate is only 50%. “Today, the treatment is essentially the same for every patient and we don’t treat the disease at the individual level. Some patients respond well to the treatments available, while others are non-responders. Dilated cardiomyopathy (DCM) is one of the most common types, and its cause is often unknown,” explains Giannetti, Chief of Cardiology and Medical Director of the Heart Failure and Heart Transplant Centre.

Giannetti is excited about the opportunity that this translational collaboration, driven by an innovative basic bioscience component, provides to transform the current generalized approach to treating and managing heart muscle disease into precision medicine.

“By modeling and understanding the disease and its progression at the individual patient and cellular levels, we want to eliminate the modifier ‘idiopathic,’ so the cause is known for every patient. If we can develop predictive biomarkers to identify people at risk of developing DCM, it could be prevented with appropriate lifestyle changes and the right medications,” says Giannetti. “Another major goal of this research is to develop new targeted therapies that can reverse the muscle disease and dilating processes that result in DCM progression.”

Giannetti and Hébert are working on the project with MUHC cardiac surgeon Renzo Cecere, BSc’86, MDCM’90, PGME’97, who will be converting patient blood samples into stem cells, and Kyla Bourque, BSc’16, a PhD student in Hébert’s lab in the Department of Pharmacology and Therapeutics, who will be developing 3D mini-hearts from the patient-derived stem cells.

Hébert’s biosensors, which light up signalling pathways in live cells, will be a key investigative tool to better understand the effects of specific genes, cell signalling patterns and cellular changes on disease progression in individual patients, and to evaluate therapeutic responses in the patient-derived cells and mini-heart models.

“Understanding the cellular signalling events that drive cardiac remodelling and heart failure in multiple cell types in the heart is critical to developing more specific treatments that are effective, with fewer undesirable side effects,” he says.

In future, Giannetti and Hebert’s biosensor-based, heart-in-a-dish platform can be applied in a personalized medicine approach to other types of cardiomyopathy and other cardiovascular diseases using patient-derived stem cells. “We also want to leverage this generously funded research to generate a larger ‘disease-in-a-dish’ consortium at McGill to facilitate organoid modelling and drug discovery in both rare and common conditions beyond heart disease,” Hébert says.

Giannetti is confident that through an improved understanding of individualized disease mechanisms, new molecular diagnostics, and targeted therapies their research could lead to improved outcomes for all those with, or at risk for, DCM.

“We want to shift from a generalized, trial and error approach to precision medicine in preventing, diagnosing, and treating heart muscle disease. These are ambitious goals, but we hope to someday reduce the number of patients with DCM undergoing transplants from 50% to less than 5%, substantially reduce the burden of DCM in the Canadian population, and hopefully cure some types of cardiomyopathy in the next 10 years,” she says.

June 30 2020