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16/7/2018

CHEO Research Institute Senior Scientists and Scientists Receive CIHR Project Grants

CHEO Researchers awarded more than $3.8M in funding to support discoveries today for healthier kids tomorrow

Martin Osmond, CEO and Scientific Director of the CHEO Research Institute and VP Research at CHEO, is pleased to share that five CHEO RI researchers have been awarded Project Grants from CIHR with another as co-Principal investigator. These funds will allow research teams to make significant strides in their research in areas such as muscular dystrophy and vaccination health outcomes. The CHEO Research Institute had a 28% success rate with our CIHR Project Grant applications for this round (five successful out of 18 applications), higher than the competition success rate of 14%. This speaks to the strength of the CHEO RI's research and grant applications and the strong collaborations with project co-investigators. Ranging from three to five years, these projects include basic science, clinical trials and a randomized controlled trial. Congratulations to Senior Scientists Bob Korneluk, Alex Mackenzie, Kusum Menon and Bill Gardner, and Scientists Deshayne Fell and Dayre McNally. We are very proud that Drs Fell and Menon ranked first in their panels while Drs Korneluk and McNally both ranked second; a truly outstanding result for CHEO RI researchers.

The grants, in order of amount awarded, are:
  • Dr. Kusum Menon for the project Stress Hydrocortisone in Pediatric Septic Shock (The SHIPSS trial) (five years, $1,101,600)
  • Dr. Dayre McNally for the project Rapid correction of vitamin D deficiency in pediatric critical illness: A phase III multicentre randomized controlled trial (five years, $983,026)
  • Dr. Robert Korneluk for the project Combined IAP antagonism and immunotherapy for cancer treatment (five years, $937,126)
  • Dr. Alexander Mackenzie for the project Pharmacologic and RNAi Screens for Myotonic Dystrophy Type 1 foci modulators; towards Novel DM1 therapeutic approaches (three years, $481,950)
  • Dr. Deshayne Fell for the project Impact of maternal pertussis immunization on pregnancy outcome and child health (three years, $336,600)
  • Dr. William Gardner as co-Principal Investigator on Equity in Mental Health Care for Children and Youth (four years, $650,251), which is led by Graham Reid at the University of Western Ontario

More information about the grants:

Dr. Kusum Menon for the project Stress Hydrocortisone in Pediatric Septic Shock (The SHIPSS trial) (five years, $1,101,600). Septic shock accounts for up to 8% of pediatric intensive care unit (PICU) admissions worldwide, carries significant morbidity and has a mortality rate between 5% and 40% depending on the geographic region in which it occurs. Mainstays of treatment involve antibiotics, fluids and medications to improve blood pressure. However, the high morbidity and mortality of pediatric septic shock have led physicians to consider corticosteroids for unstable patients since corticosteroids are inexpensive and widely available. However, although the use of corticosteroids for septic shock has been widely debated for over 40 years, there is no clear evidence for or against this practice. Some pediatric studies have reported an improvement in blood pressure and organ function with corticosteroids while other studies have suggested an increase in blood sugar and the inability to fight infection. We therefore plan to conduct a randomized controlled trial to determine if hydrocortisone (a corticosteroid) compared to placebo improves outcomes (as measured by mortality and quality of life) in children with septic shock. This study will enroll 1032 patients in 30 centres across Canada and the US. Eligible children will include those from age 1 month to 17 years, with a severe infection and need for medications to support their blood pressure. We will exclude patients that have a known reason for receiving corticosteroids, who have malaria or a fungal infection and those who do not wish to participate. We will also assess organ function, potential side effects and healthcare costs in the hydrocortisone and placebo groups. Our study will be the first pediatric septic shock trial that is large enough to assess the potential benefits of corticosteroids and the first trial to assess the effect of a treatment for septic shock on quality of life. The results of this study will provide evidence on which to base recommendations for corticosteroid administration in pediatric septic shock.

Dr. Dayre McNally for the project Rapid correction of vitamin D deficiency in pediatric critical illness: A phase III multicentre randomized controlled trial (five years, $983,026). Vitamin D plays an important role in calcium balance, heart and lung health, inflammation, infection prevention, and muscle strength. Due to these roles, it has been suggested that critically ill patients with low levels might have higher rates of death and worse long term health. We believe that identifying critically ill children with vitamin D deficiency and then restoring vitamin D levels quickly could represent a safe, easy and inexpensive means of reducing patient illness, preventing death and improving quality of life. This application seeks funding for a clinical trial that will determine whether rapid normalization of vitamin D deficiency improves survival and health-related quality of life following critical illness. The project is designed as a multicentre trial in ten Canadian Pediatric Intensive Care Units. Critically ill children who agree to participate (consent given by caregivers) will have their blood vitamin D level measured, and those who are deficient will be randomized to receive a single dose of either high dose vitamin D3 or placebo (no drug). Study participants assigned to the high dose vitamin D arm will receive 10000 IU/kg of enteral cholecalciferol (up to a maximum of 400000 IU). We have tested this dose in a pilot trial, and no patient experienced serious adverse events related to vitamin D administration. Patients will be followed for 90 days to determine whether they survived and had a significant change in their health and quality of life. Vitamin D deficiency is a common problem not only among critically ill Canadian children, but in PICUs worldwide. In addition to being applicable in Canada, our study protocol has been designed to be generalizable and meaningful to critically ill children worldwide.

Dr. Robert Korneluk for the project Combined IAP antagonism and immunotherapy for cancer treatment (five years, $937,126). Immunotherapy is currently an effective and viable treatment for several cancers and this approach complements the existing standard treatment modalities of surgery, radiation and chemotherapy. The recent successes of immunotherapy agents (known as immune checkpoint inhibitors or ICIs) for metastatic and refractory, advanced-staged cancers have ushered in a new treatment era for melanoma, lung, renal and bladder cancer, to name a few. It is expected that the maximal benefit of cancer immunotherapy will only be derived from combination approaches that allow for additive or synergistic effects to mount a full-blown immune attack against the cancer, and that block the development of resistance to immunotherapy. Our results to date, and the aims outlined in this proposal, will provide information for a novel and effective combination immunotherapy for cancers that combines an ICI with a drug, known as a Smac mimetic compound (SMC), which targets the inhibitors-of-apoptosis (IAP) proteins. The IAPs were identified by our group over 20 years ago and are now known to be important cancer causing genes. Our progress over the last four years, in experimentally validating the effectiveness of this combination approach, has laid the foundation for the initiation of appropriate clinical trials. In fact, we have recently begun a clinical trial in November of 2017 under the direction of our clinical colleague, Dr. Glenwood Goss at the Ottawa Hospital, in which he will be combining an ICI with a SMC to treat lung cancer patients. This CIHR proposal seeks to further understand the mechanisms of SMC/ICI combination synergy in eradicating various cancers using animal models. Our proof-of-principle studies will improve our understanding of cancer and ultimately see the translation of these combinations into the clinic to treat cancer.

Dr. Alexander Mackenzie for the project Pharmacologic and RNAi Screens for Myotonic Dystrophy Type 1 foci modulators; towards Novel DM1 therapeutic approaches (three years, $481,950). Myotonic Dystrophy Type 1 (DM1) is the most common form of adult muscular dystrophy affecting as many as 1 in 500 people in some regions of Quebec. DM1 can manifest ininfancy, in old age or at any stage in between affecting all systems in the body including eyes, heart, brain and muscle (myotonia). Infants with DM1 often do not survive due to weak lungs and insufficient breathing; those who survive are usually affected by intellectual delay. Cells from DM1 patients when studied under the microscope reveal bright spots known as RNA foci. These foci are products of the mutated DM1 gene; in addition to helping make the diagnosis of the DM1, it is believed that these bodies interfere with normal cell function and are thus involved in causing the disease itself; the foci are in this sense a therapeutic target. When these aggregates are broken apart, proper cellular function is often restored, making "foci busters" good candidates for DM1 therapy. We shall therefore treat DM1 patient cells with thousands of compounds, including hundreds of currently used FDA-approved medications and using automated microscopy looking for reduction of these aggregates. Similarly we will interfere with 1000’s of genes in the body and look for similar impact. Importantly we will use muscle cells from DM1 patient to do this test. Drugs and genes which reduce the number and or size of aggregates will be next tested in a mouse genetically engineered to have DM1 which display signs similar to that seen in humans. We will compare untreated and drug-treated mice to determine if the medications improved their DM1 signs. If treated animals show improved signs; this information could be used as the basis for a clinical trial. Using medications which are already in use for other conditions is advantageous as it by-passes the significant time required for safety and efficacy testing of newly developed drugs, saving both time and money.

Dr. Deshayne Fell for the project Impact of maternal pertussis immunization on pregnancy outcome and child health (three years, $336,600). Pertussis (also known as whooping cough) is a highly contagious infectious illness that mainly affects the lungs. The highest risk of severe pertussis illness occurs in babies under the age of two months, and can lead to breathing difficulties, hospitalization, and even death. In order to prevent these early cases, women are sometimes vaccinated against pertussis during their pregnancy, which provides protection to the babies before they are fully vaccinated themselves in the early months of life. However, even in countries where pertussis vaccination is recommended and provided for free, not all pregnant women become vaccinated possibly due to ongoing concern about the benefits and safety of vaccination during pregnancy for their children. As there is limited information on possible benefits or concerns of pertussis vaccination during pregnancy on longer-term health, our study will examine important health outcomes among children up to six years of age. Our findings will provide valuable information to pregnant women and their families, as well as to health care providers working to ensure that mothers and their children are in the best possible health. (Co-Principal Investigators: Shelly Bolotin and Natasha Crowcraft.)

As well, Dr. William Gardner is a co-Principal Investigator on Equity in Mental Health Care for Children and Youth (four years, $650,251), which is led by Graham Reid at the University of Western Ontario. Mental health problems and suicide are among the most important causes of morbidity and mortality for children and youth. Yet access to mental health care for children is an ongoing challenge. The principle of equity in access to healthcare is reflected in the Canada Health Act. However, equity in access to MH care is ill-defined and has rarely been examined in relation to child/youth mental health services (CYMHS). The current study will conduct a systematic review of how equity has been evaluated with respect to MH care for children and youth. Equity can be defined as equal access to services. Within Ontario and across Canada, specialized MH and psychiatric services for children and youth are delivered mainly through publicly-funded agencies and psychiatrists. Private providers (psychologists and social workers) also play a role; we have little information on the role that private providers play in the systems that care for this population. The present study will also examine the distribution of publicly-funded agencies, psychiatrists, and private providers, and the extent to which sociodemographic factors (e.g., family income) are related to the distribution of child and youth MH services. If the distribution of agencies, psychiatrists, and private providers varies by regions, this would likely result in inequity in access to care for individuals in regions with fewer agencies/providers. Second, if the distribution of agencies, psychiatrists, and private providers varies by region as a function of sociodemographic factors, it would also reflect inequities in access to care. Identification of inequity is the first step to addressing those inequities and ultimately improving the systems in place to care for children and youth with mental health problems. (Co-PI: Graham Reid.)

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