Freshly funded: Congratulations to Dr. Seema Mital and Dr. Marcelo Cypel
The CDTRP wishes to congratulate Dr. Seema Mital and Dr. Marcelo Cypel and their teams at UHN for their success in the CIHR Fall 2020 competitions.
Dr. Seema Mital’s Project:
A Role for novel regulatory variants in childhoood cardiomyopathy (link here)
Cardiomyopathy is a genetic disease of heart muscle and the leading cause of heart failure and sudden cardiac death in children. It is inherited in families in at least a third of cases. Despite availability of genetic testing, the genetic cause of the majority of cardiomyopathies remains unknown since current tests only look for defects in a small number of known genes in the genome that code for proteins important in heart structure and function. Whole genome sequencing allows a search for defects in previously unexplored genes i.e. non-coding regions of the genome that control amount of gene and protein available. Using whole genome sequencing, we identified new genomic defects (or mutations) not previously reported in patients with cardiomyopathy. The purpose of this project is to test the effect of these mutations in heart cells from patients with these defects to determine if they negatively affect the function of heart cells similar to patients with cardiomyopathy. Also, using gene-editing, we will correct the mutations in these cells to see if they rescue the disease. We will use these cells to test which drugs can improve the function of the heart cells. By showing that these novel mutations cause cardiomyopathy, our study will improve the understanding of the genetic basis of cardiomyopathies. It will also help genetic testing laboratories to expand their genetic tests to include a search for novel variants in non-coding regions of the genome. Identifying the genetic cause of disease in more patients will help us to offer genetic screening to a greater number of affected families which will allow earlier diagnosis and timely interventions in family members to prevent sudden death and progression to heart failure. Results of our drug tests will provide insights into new drug development for this serious condition.
Dr. Marcelo Cypel’s Projects:
Establishing strategies to preserve donor lungs for multiple days: Cyclic Normothermic Ex Vivo Lung Perfusion and Mitochondrial Transplantation (link here)
Currently, lungs donated for clinical transplantation are preserved in an ice cooler where the organ rests at a temperature of around 4°C. Due to the potential injuries manifested during the preservation period, transplant surgeons adopt a conservative approach of only 4-6h of total preservation time. Recently, we have shown that by preserving the lungs at 10°C (rather than 4°C), the preservation window can be significantly extended without comprising organ quality. However, even under these conditions, organ viability eventually deteriorates, and the lungs are no longer suitable for transplantation. Therefore, novel approaches are required in order to extend further organ preservation periods, which would, in turn, have several important implications in the field of lung transplantation. Longer preservation times will allow for the opportunity to match donors and recipients better, overcome geographical hurdles faced in organ donation, and, importantly, the progression of lung transplantation towards a scheduled- instead of an urgent – procedure. Another advantage in safely prolonging organ preservation will be the ability for many patients to stay at their home city while waiting for an organ rather than re-locating to the city of the transplant hospital with many social and financial advantages. To achieve this, we will combine the 10 °C storage with cycles of normothermic ex vivo lung perfusion (EVLP). EVLP is a revolutionary technology that allows for the simulation of physiological conditions outside of the body. During EVLP, lungs are brought back to human body temperature, provided with oxygen and nutrition, and metabolism is restored. To understand the benefit of this approach, we aim to fully characterize cell metabolism and mitochondrial health, thus elucidating mechanisms and pathways of lung damage and recovery.
Ex vivo treatment of latent human cytomegalovirus in donor lungs using F49A-Fusion protein: Pre-clinical studies and a safety pilot clinical trial (link here)
Lung transplantation is a life-saving intervention for people with advanced lung diseases. However, because transplant recipients have their immune system medically depleted, they are at a significant risk of acquiring viruses carried by the transplanted organ, resulting in life-threatening infections. Human cytomegalovirus (CMV) is the most prevalent viral infection after lung transplantation. We developed a stable assessment system to maintain donor lungs outside of the body prior to transplant so that novel treatment strategies can be applied to clear this virus in the donor organ before surgery. This system is called ex vivo lung perfusion, or EVLP. We propose investigating an innovative targeted drug added to the EVLP circuit to eliminate CMV from the organ in the laboratory. We will also investigate the safety of this treatment before transplant into patients in a clinical study. If successful, outcomes of life- saving lung transplantation will be greatly improved.