Team Projects – Cycle 2 (2019-2022)

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.

Project Overview: There is keen interest in the environmental signals within stem cell tissue niches that promote tissue repair in settings 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.

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.

Project Overview: The immune system remains one of the major barriers to effectively translate the advances in the generation of stem cell-derived tissues to treat/cure degenerative diseases. Successfully hiding cells from functional immune system will eliminate the need for immune suppression of patients of cell therapies. Combining with the safe cell platform strategy will abolish the inherent risk of cloaked cells to form tumours.

This project will develop advanced cellular and molecular approaches to treat or even cure a broad set disease. Our prototype disease is type1 diabetes (T1D). T1D is autoimmune in nature, where the diabetic’s own immune system attacks and kills insulin-producing β-cells. The attempts to replace the lost β-cells with transplanted cells are challenged by the ongoing autoimmunity, as well as by inflammation, stress, cell death, and alloreaction in the case of transplanted cells that are not host-derived. Our immune cloaked and safe cells will give a solution to the challenge and hold promise to treat T1D.

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.

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.

Project Overview: The establishment of human cerebral organoids (hCOs) from human pluripotent stem cells (hPSCs) has revealed morphogenetic processes that recapitulate unique features of human brain development. Organoids can thus facilitate the dissection of mechanisms underlying tissue dynamics in development and disease and bridge the gap between traditional 2D cell culture and in vivo genetic animal models.

This project will build upon this team’s previous work to characterize vascularized hCOs using a novel microfluidic platform combined with single cell profiling and tissue imaging. The establishment of robust, vascularized hCOs will be leveraged to develop more physiologically relevant pre-clinical human models of neurological diseases and disorders, including the identification of neurotoxicity and drug penetration through the blood-brain barrier. These studies will lead to a deep understanding of the development of human neural systems and their response to injury, provide new pre-clinical tools that will drive more efficient and safer drug development, and illuminate potential therapeutic strategies to treat stroke.

Project Overview: The project will investigate strategies to prevent the immune system from rejecting transplanted tissues derived from stem cells — a key challenge for regenerative medicine. Their team is using as its model stem cell-derived beta cells — pancreatic cells that produce insulin — which are being widely studied as a possible regenerative medicine therapy for diabetes. ​