Ottawa, Ontario — Wednesday February 8, 2023
The CHEO Research Institute, one of the top 40 research hospitals in the country, is pleased to announce that two of its projects received Canadian Institutes of Health Research (CIHR) grants as part of the Fall 2022 Project Grant competition, and two were funded as priority announcements.
The CHEO Research Institute had a 25% success rate in this competition (CIHR average is 20.1%).
The CHEO Research Institute projects will improve understanding of Shwachman Diamond syndrome (SDS), whose patients are at a much higher risk of developing high-risk types of leukemia, and how well baseline MRI markers predict subsequent lung health and development of pre-mature babies. The priority announcements contribute to key areas of CIHR focus being breast cancer research and patient-oriented research: early-career investigator.
The successful CHEO Research Institute projects are:
Identifying novel strategies for leukemia prevention using zebrafish models of dnajc21-mutant Shwachman Diamond syndrome
Principal Investigator: Jason Berman
Co-investigators: Dror, Yigal; Ketharnathan, Sarada
Amount/term funded: $910,350 over 5 years
Overview: Shwachman Diamond syndrome (SDS) is a type of bone marrow failure that frequently presents in children and young adults. It results in poor growth, reduced production of white blood cells and pancreatic dysfunction. SDS is caused by abnormalities in genes, including one called DNAJC21, which play important roles in assembling ribosomes that are required in all cells to make proteins. SDS patients are at a much higher risk of developing high-risk types of leukemia. Current definitive treatment for SDS requires a bone marrow transplant and is associated with many potential complications and risks. There is an unmet need for developing treatments that are specific to SDS biology that could help restore normal blood cell numbers with the goal of preventing the development of leukemia. The zebrafish has very similar but more rapid blood development than humans, making it an ideal animal model for studying SDS and how it evolves into leukemia. Our laboratory has extensive experience in this area, and we have already developed zebrafish carrying mutations in the zebrafish DNAJC21 gene. These mutant fish have stunted growth and reduced white blood cell production similar to SDS patients. To model leukemia progression, we have introduced additional mutations in genes frequently seen in SDS patients with leukemia. We believe that the metabolism level of these blood cells is low when the bone marrow isn’t working well and becomes high when it develops into leukemia. We will investigate if these metabolic factors can be targeted to stop leukemia progression. Lastly, we will use cells from SDS patients to check for the genetic changes that we find in our zebrafish and look for drugs that can rescue blood defects and potentially halt the development of leukemia. This study will improve our understanding of SDS and other conditions that increase the risk of developing leukemia and identify drugs for leukemia prevention.
Early-life MRI biomarkers of longer-term respiratory morbidity in infants born extremely preterm (EMBLEM)
Principal Investigator: Sherri Katz; Giles E. Santyr
Co-investigators: Abdeen, Nishard; Altit, Gabriel; Barrowman, Nicholas J; Ben Fadel, Nadya; Gorgos, Andreea; Greer, Mary-Louise; Jain, Amish; Lands, Larry C; Lapointe, Anie; Lee, Suzie; Luu, Thuy Mai; Mohamed, Adel; Moraes, Theo; Nguyen, The Thanh Diem; Nuyt, Anne Monique; Parraga, Grace; Raghuram, Kamini; Shah, Prakeshkumar; Thebaud, Bernard; Vogel-Claussen, Jens; Voskrebenzev, Andreas
Amount/term funded: $1,202,005 over 5 years
Overview: Bronchopulmonary dysplasia (BPD) is a common, major complication of premature birth, associated with developmental and health consequences that continue into adulthood. Prediction of who will have these problems is challenging using traditional definitions of disease. It is believed that underdevelopment and injury occur in both lung tissue and the blood vessels in the lungs, with a sophisticated interplay between them that contributes to lung disease seen in prematurity. New magnetic resonance imaging (MRI) techniques can delineate tissue structure with unprecedented granularity, assessing lung tissue, blood vessels and their interplay. The ability to identify, at an early stage, those infants destined for chronic lung disease with greater certainty will be useful in counselling families and critical for effective introduction of promising new BPD therapies. 319 infants born less than 29 weeks gestation will be recruited from 4 Canadian centres, including 5 babies who will receive stem cell therapy as part of a separate clinical trial. Babies will be evaluated at 36 weeks post-conception with lung MRI, oscillometry (lung function), echocardiogram (heart ultrasound) and lung ultrasound. Lung health will be assessed every 3 months by phone questionnaire and chart review. At 18-21 months post-conception, babies will undergo neurodevelopmental assessment and oscillometry. We will look at how well baseline MRI markers predict subsequent lung health and development, independently and combined with echocardiogram, lung ultrasound and traditional markers of BPD. We anticipate that these new MRI markers will provide safe, robust measures of present and future lung health in preterm-born babies. By identifying predictors of longer-term lung disease, clinicians will be able to allocate resources to babies at highest risk. Further, we envision that MRI will help identify babies who would benefit most from stem cell and other therapies, as well as measure treatment effects.
Viralyzing transgenes to improve oncolytic immunotherapy (breast cancer research)
Principal Investigator: Tommy Alain, Tyson Graber
Co-investigators: Hoang, Dung H
Amount/term funded: $100,000 over 1 year
Overview: Cancer killing viruses carry a “payload” as a form of a “transgene”. This payload is critical for their anti-cancer efficacy. The transgene is often a carbon copy of a human gene, but we know that the human genetics is very different to that of a virus. This is like putting a Ford F150 engine into a Ferrari, it can work but it will not be ideal for the chassis. Our goal is to achieve maximal “payload” expression from “transgenes” encoded by oncolytic viruses – viruses geared towards cancer immunotherapies. We want the most bang for our bucks with these critical therapeutic payloads, so every part needs to be perfectly aligned with the machine. Every virus is unique and we will characterize the distinct blueprints that will provide the greatest powertrain for the transgene and virus, here Herpes Simplex Virus and Vaccinia Virus. Transgenes encoded within viral genomes are mostly taken from the exact coding sequence of human genes. However, many regulatory elements exist within 5’leaders and it is well-known that the codon sequence is critical for high expression. Furthermore, genome location can have many implications. Viruses are unique in their 5’leader, codon usage, and genome organization. The project describes our approach to obtain maximal payload expression by “viro-optimizing – Viralyzing’ every parts of the transgenes. Oncolytic viruses are little but extremely powerful machines that can have massive impact for cancer immunotherapies. More than 150 viruses are currently under investigation in labs and companies around the world. For best responses, these viruses are all upgraded with a payload, but this addition has surprisingly not been optimally encoded for their unique racing machine. This project aims to turbocharge transgene expression and apply our findings to clinically relevant cancer virotherapies. Patients want the best machine available and our optimal transgene program will put their oncolytic virus of choice in the pole position.
Better Together: Identifying Collaborative Research Priorities and Literature Gaps in Child Maltreatment Research (patient-oriented research: early-career investigator)
Principal Investigator: Nicole Racine, Joanna Henderson, Rebeka Nicholson
Co-investigators: Collin-Vézina, Delphine; Dimitropoulos, Gina; Doucet, Melanie M; Garfinkel, Daniel; Hartwick, Cailey; Labelle, Patrick R; Madigan, Sheri L; Restrepo, Maria A; Sawyer, Kafui
Amount/term funded: $100,000 over 1 year
Overview: One in three children in Canada has been exposed to child abuse or neglect, which can lead to the development of negative physical health and mental health outcomes across the lifespan. With heightened family stress during the COVID-19 pandemic, risk factors for child abuse increased, leading to even greater mental health challenges and support needs. Research priorities that capture the perspective of youth and caregivers who have experienced abuse and neglect are thus urgently needed. In line with the saying “nothing about us, without us”, youth and caregivers with lived experience need to be included in research priority setting in order for research to be relevant, efficient, and cost-effective. The goal of the Better Together project is to create partnerships between youth, caregivers, clinicians, and researchers to identify key research priorities to guide the future of child maltreatment research in Canada. Using a co-design research approach, we will work with individuals with lived experience to identify and prioritize how to improve mental health and adaptive outcomes following exposure to child abuse and neglect. We will achieve this goal in four main ways: 1) we will identify the most important research questions about child maltreatment from the perspective of diverse stakeholders, 2) we will identify key literature gaps in etiology, assessment, treatment, and prevention of child maltreatment, 3) we will develop a collaborative “top ten” list of the most important research priorities which will be shared nationally and internationally, and 4) we will explore how youth, caregiver, clinician, and researcher perspectives on patient engagement shift over the course of the project. Individuals with lived experience will be involved at each step of the process. The Better Together project will share and disseminate what we learn with researchers and clinicians across Canada to inform the co-design of new interventions and improvements in mental health.