Targeting defective muscle stem cells to mitigate myotonic dystrophy type 1
Nicolas Dumont, Elise Duchesne, Christian Beauséjour
Myotonic dystrophy type 1 (DM1) is the most frequent genetic myopathies in adult. The diseaseMyotonic dystrophy type 1 (DM1) is the most frequent genetic myopathies in adult. The diseaseis characterized by progressive muscle atrophy and weakness. DM1 also affects the regenerativecapacity of muscle stem cells, the engine of muscle repair. Thus, there is a strong therapeuticpotential to develop strategies targeting defective muscle stem cells for the treatment of DM1;however, this avenue remains unexplored. Our goal is to determine the therapeutic potential ofnovel therapeutic molecules aiming at eliminating defective muscle stem cells to mitigate DM1.Our first objective is to carefully characterize the cellular defects in muscle stem cells collectedfrom patients with DM1. Next, we will test a series of molecules with the potential to eliminatedefective cells, in order to assess the impact on the regenerative capacity of the muscles. To doso, we will use models of in vitro cell culture and in vivo cell transplantation. This project willallow to better understand this genetic muscular disease and will pave the way for a newtherapeutic avenue that could improve muscle healing and slow the progression of the disease.
Extracellular vesicles for delivery of the components of the CRISPR/PRIME genome editingtechnology.
Jacques P. Tremblay, Véronique Moulin, Janusz Rak
Our research project aims to develop a new technique to deliver proteins or mRNAs allowingOur research project aims to develop a new technique to deliver proteins or mRNAs allowingspecific modification of a gene. This new technique uses extra-cellular vesicles. Thesevesicles can be isolated from cell culture medium or from plasma. We will develop techniquesthat will allow the introduction of a pegRNA and proteins or mRNAs into these vesicles. Theseagents make it possible to modify genes very precisely and can therefore be used to correctvery small mutations (only one nucleotide) responsible for hereditary diseases or cancers or tostop production of a protein at the origin of pathologies. These extra-cellular vesicles will be acheaper delivery method for gene therapy than the Adenovirus Associated Viruses (AAVs)currently used for gene therapy. Once the transfer system will be developed, we plan to test itin order to set up a treatment for two rare and incurable diseases: Duchenne dystrophy andsystemic scleroderma.
BK-specific T-cell immunotherapy; moving towards a clinical trial
Caroline Lamarche, Jean-Sébastien Delisle, Jean-François Cailhier
BK polyomavirus is usually an inoffensive virus that hides in kidneys, held in check by our immune system. However, in kidney transplant recipients, it can reactivate and lead to a decrease in graft function and even graft loss. There is currently no effective and safe treatment for this condition. We believe the best treatment would be cell therapy i.e to give back the ability to fight and control this virus using the patient’s own immune system. We previously showed that this technique is feasible and safe in a lab. The goal of this proposal is to set the foundation to move to the first clinical trial by fulfilling the data needed in order for Health Canada to approve our study. We are aiming to do the first multicenter, CanadianBK polyomavirus is usually an inoffensive virus that hides in kidneys, held in check by our immune system. However, in kidney transplant recipients, it can reactivate and lead to a decrease in graft function and even graft loss. There is currently no effective and safe treatment for this condition. We believe the best treatment would be cell therapy i.e to give back the ability to fight and control this virus using the patient’s own immune system. We previously showed that this technique is feasible and safe in a lab. The goal of this proposal is to set the foundation to move to the first clinical trial by fulfilling the data needed in order for Health Canada to approve our study. We are aiming to do the first multicenter, Canadianstudy using cell therapy for this condition. We will establish the clinical protocol with different centers within Quebec and patient partners, transfer the manufacturing protocol in a cellular therapy center (CETC) and do the necessary tests to obtain Health Canada’s approval. Theobjectives are fully in line with ThéCell mission as it is a transfer of fundamental knowledge toclinic, creation of a network of collaborators and promotion of cell therapy.
Generation of isogenic cell lines for GNA11/BAP1 mutations by “PRIME editing” as study models for ocular melanoma.
Solange Landreville, Jacques P. Tremblay, Sonia Del Rincon
Acquisition of mutations in choroidal melanocytes leads to uveal melanoma (UM), the most frequentAcquisition of mutations in choroidal melanocytes leads to uveal melanoma (UM), the most frequentprimary intraocular cancer in adults. Half of the patients develop incurable liver metastases.Majority of UMs have an early mutation in the GNAQ or GNA11 genes, resulting in cell proliferation.The BAP1 gene is mutated in a majority of metastatic UM cases. Our hypothesis is that BAP1-mutantmetastatic cells or their extracellular vesicles (EVs) can inhibit the activity of T-cells in liver metastases.To delineate the role of BAP1 loss in the immunosuppressive potential of metastatic cells, our specificresearch aims are: 1) to generate isogenic cell lines for GNA11/BAP1 mutations using PRIME editing;2) to compare their invasive and immunoregulatory potentials using 3D and animal models.We expect that BAP1-mutant metastatic cells or EVs will modulate the expression of immunoregulatoryproteins in the hepatic microenvironment, which will impact the anti-tumorigenic activity of T-cellsagainst metastases. Our study will provide i) an in vitro model that mimics the different stages of UMprogression without the complexity of clinical samples, and ii) a better understanding of immune-escapemechanisms driven by UM cells.
Granulocyte Transfusions: Optimization of Granulocyte Concentrate Storage and Role of Monocytes
Maria Fernandes, Renée Basin, Sylvie Lesage
Life threatening infections in patients whose immune system is no longer able to protect them canLife threatening infections in patients whose immune system is no longer able to protect them canbe treated with a cell therapy product known as granulocyte concentrates. This cell therapy providespatients with neutrophils; immune cells that are masters at destroying infectious microbes.One of the challenges in the preparation of granulocyte concentrates is to maintain all theneutrophils alive and healthy during storage. We will, therefore, modify the storage conditions of thiscell therapy product to provide optimal conditions for neutrophil survival and preservation ofneutrophil anti-microbial defenses.Neutrophils do not act alone, they team up with another immune cell known as the monocyte toeliminate intruders in our bodies. Although granulocyte concentrates also contain monocytes, we donot know how monocytes react to the storage. We will, therefore, determine how the storage ofgranulocyte concentrates affects monocytes function and survival and use this new knowledge todevelop the best storage conditions for these cells too.This research addresses a key goals of ThéCell, improving the quality of cell therapies. We aim toimprove a cell therapy product produced by Héma-Québec to increase its efficacy at saving the lives ofpatients with life-threatening infections.
Engineering a vascularized immunoisolation device to treat diabetes: assessing pseudo-islet function
Corinne Hoesli, André Bégin-Drolet, Jianyu Li
Type 1 diabetes is an autoimmune disease where the immune system attacks theType 1 diabetes is an autoimmune disease where the immune system attacks theinsulin-producing beta cells of the pancreas. People suffering from this disease control theirblood glucose levels using insulin injections or infusion. Even with scientific progress in thisfield, this approach leads to risks of hypoglycemia (glucose to low) and cardiovascularcomplications.Instead of injecting insulin, islet transplantation is a long-term therapeutic approach based onreplacing the beta cells and re-establishing endogenous insulin production. Our teamperformed the first islet transplants in Québec. Over 70% of the patients receiving islet graftswill live without needing insulin injections for at least two years. Access to this therapy islimited by donated organ supply. Moreover, the immune suppression medication required toavoid graft rejection is associated with unwanted side effects.The goal of this research project is to design a transplantation device to avoid islet rejectionand enable the use of stem cells instead of islets from organ donors. This device would avoidthe need for immune suppression, improve treatment outcome and increase the number ofpatients that have access to this cellular therapy.