Spanning stem cell therapy, endogenous repair, gene therapy and the creation of new technology, Medicine by Design’s Cycle 2 (2019-2022) research program leverages the advantages of large‐scale, multi‐institution funding and combines advances in new technology with important biological questions to achieve translatable outcomes.

Medicine by Design is investing as much as $20 million in as many as 12 Cycle 2 projects. The following seven projects have been approved for funding:

Cardiac regeneration using pluripotent stem cells

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Lead Investigator:
Dr. Michael Laflamme
McEwen Stem Cell Institute, University Health Network

Co-Investigators:
Hai-Ling Cheng, Dr. Slava Epelman, Mark Friedberg, Nilesh Ghugre, Anthony Gramolini, Scott Heximer, Gordon Keller

Project Overview: This team is capitalizing on the world-leading effort in Toronto to “re-muscularize” injured hearts with hPSC-derived cardiac muscle (CM) grafts, transforming the treatment of heart failure from one of disease management to one that is truly restorative. Bringing together researchers from the University Health Network, Sunnybrook Health Systems, SickKids Research Institute, and U of T, this team is poised to initiate a first-in-human clinical trial to test their hPSC-based cardiac cell therapy.

Medicine by Design is ensuring they stay at the forefront of this effort by leveraging funding from the Ted Rogers Centre for Heart Research and BlueRock Therapeutics to further invest in this work, with a focus on overcoming the critical remaining barriers to translation by developing “next-generation” hPSC-derived cardiac muscle cells to improve graft integration, survival, function and non-invasive monitoring. These hPSC-CM grafts will also be evaluated for a new application – to support the right ventricle under high pressure, which is the predominant heart failure mechanism in pulmonary hypertension and congenital heart disease, a major pediatric indication.

Stem cell-based approaches to endogenous repair of brain and skeletal muscle

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Lead Investigator:
Freda Miller
The Hospital for Sick Children

Co-Investigators:
Gary Bader, Penney Gilbert, Sid Goyal, David Kaplan, Yun Li, Alison McGuigan, Cindi Morshead, Peter Zandstra

Project Overview: There is keen interest in the environmental signals within stem cell tissue niches that promote tissue repair insettings where regeneration does not occur naturally. To date, studies to identify these signals have been conducted in an inefficient and non-robust manner, examining one signal at a time, hand-picked from large datasets, in expensive preclinical animal models.

In this project, candidate therapeutics (novel small molecules and/or re-purposed drugs) for endogenous stem cell-mediated repair of brain demyelinating disorders and muscular dystrophy will be identified using revolutionary molecular screening approaches that apply high-throughput single cell transcriptomics and computational modeling to predict the signals that exert responses of interest (e.g. repair-like activity) and then validating these combinations in rapid, experimentally amenable and accurate in vitro models of human brain and muscle stem cell tissue.

Targeting mesoderm differentiation bottlenecks for regenerative therapies

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Lead Investigator:
Shana Kelley
Leslie Dan Faculty of Pharmacy

Co-Investigators:
Stephane Angers, Ben Blencowe, Alison McGuigan, Jason Moffat, Keith Pardee, Sachdev Sidhu, Aaron Wheeler

Project Overview: Stem-cell based therapies have the potential to regenerate and repair diseased or damaged tissues in a variety of conditions, however a major hurdle to advancing these therapies is the high-cost of manufacturing the cell type of interest at the required yield and purity to achieve an efficacious and economically viable treatment.

This project is addressing this challenge by uncovering the roots of cellular heterogeneity during stem cell differentiation by combining genome-wide CRISPR and reporter-based screening approaches with high-throughput microfluidics-based profiling to guide the development of biologic reagents that enable robust on-cell screening platforms for the isolation of novel antibodies, and synthetic biology approaches for engineering therapeutic proteins.

Development of novel cell and tissue therapies to treat liver failure

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Lead Investigator:
Gordon Keller
University Health Network

Co-Investigators:
Gary Bader, Christine Bear, Axel Guenther, Sonya MacParland, Ian McGilvray, Molly Shoichet

Project Overview: The development of an hPSC-derived cell/tissue therapy to treat liver failure depends on the generation of cells and/or engineered tissue that can efficiently engraft and restore liver function. Efforts to develop protocols to promote differentiation and development of hepatocytes have been hindered by the limited repopulation potential of this cell population. A major factor contributing to this limitation is the lack of a detailed understanding of the primary cell type(s) that mediate(s) hepatocyte engraftment.

Led by a world-leading team of researchers with expertise in stem cell and liver biology, tissue engineering, liver transplantation and bioinformatics, this project aims to understand the liver’s unique ability to regenerate in order to develop effective strategies for engineering liver tissue constructs for therapeutic applications targeting liver failure. Molecular profiling of primary liver tissue aims to identify a liver repopulating cell, which will be tested in mouse transplantation studies. Co-transplantation of supportive cells to test their ability to either promote hepatocyte engraftment and repopulation in the liver, or actually regenerate specific cell types in the liver, will be tested. This team will also work on developing an advanced hPSC-derived liver organoid with rudimentary bile ducts that can provide stable liver function following ectopic transplantation.

Gene therapies to promote neuroregeneration and enhance neuroplasticity

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Lead Investigator:
Cindi Morshead
University of Toronto

Co-Investigators:
Isabelle Aubert, Maryam Faiz, Carol Schuurmans, Melanie Woodin

Project Overview: Building on combined expertise in cell and molecular biology, genetics, gene therapy, central nervous system regeneration, disease models, and behavior analyses, this team will develop broadly applicable and clinically relevant genetic reprogramming strategies to generate astrocytes and neurons as a treatment for central nervous system injuries and neurodegenerative disorders, for which there are currently no known cures.

Using a chemogenetics neuromodulation approach in pre-clinical stroke and Amyotrophic Lateral Sclerosis models, focused ultrasound will be used to activate designer receptors exclusively activated by designer drugs (DREADDs) in specific neurons to regulate excitation/inhibition activity as a strategy to restore damaged neural networks. The team will also explore cell reprogramming approaches, delivering transcription factors to astrocytes and neurons in their pre-clinical models to track effects on disease progression and neural repair. To support clinical translation efforts, hPSC-derived 3D cerebral organoids will be used to optimize and “humanize” the approach.

The endothelial-macrophage niche: A novel concept in the regulation of macrophage abundance and phenotype in tissue homeostasis, injury and regeneration

Lead Investigator:
Clint Robbins
University Health Network

Co-Investigators:
Myron Cybulsky, Jason Fish

Project Overview: Endogenous repair of the vasculature in the setting of chronic disease is impaired by the presence of systemic cardiovascular risk factors (e.g. smoking, diabetes). The lack of regeneration of the aorta, the largest blood vessel in the human body, is particularly problematic, with degeneration leading to Abdominal Aortic Aneurysm. Understanding the molecular mechanisms that control “anti-regenerative” vascular micro-environments are needed if new strategies to regenerate the aorta and reverse aneurysm progression are to be developed.

In this project, the role of local communication between endothelial cells (ECs) and macrophages (Mφs) during arterial homeostasis, injury during disease and the healing process will be studied.  Specifically, the role of EC-derived factors in maintaining the EC-Mφ niche in a model of aortic aneurysm formation will be evaluated with a view to identifying mechanisms of cell-cell communication between healthy versus dysfunctional ECs and Mφs. The insights gained from these studies will inform therapeutic strategies to promote a pro-regenerative micro-environment to stimulate repair with relevance to other vascular beds including the heart, lung, pancreas and liver.

Paving the way for endogenous repair with exogenous delivery: Investigating material exchange, synaptic connectivity and paracrine signalling in neuron transplantation

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Lead Investigator:
Molly Shoichet
University of Toronto

Co-Investigators:
Julie Lefebvre, Derek van der Kooy, Valerie Wallace

Project Overview: The goal of this project is to tailor and improve transplant outcomes from cell-based retinal therapy to achieve photoreceptor preservation, replacement and vision repair. By leveraging innovations in stem cell and transplantation biology, and novel approaches to synaptic connectivity and biomolecule delivery, this team will investigate the therapeutic benefit of cytoplasmic material exchange from transplanted human photoreceptors, develop tools to detect and promote human photoreceptor synaptic connectivity and integration for vision restoration, and deliver exogenous paracrine factors to the retina to enhance host photoreceptor survival.