Eight projects awarded $2.4 million to advance Precision Child Health

Drs. Tamorah Lewis (SickKids) and Celine Thibault (CHU Sainte-Justine) will investigate the interaction between pharmacogenetics and pharmacokinetics of various drugs to enhance safety and improve the effectiveness of therapies. Their studies will also provide better guidance on dosages for neonates and infants in intensive care.

Their study will recruit infants from both hospitals to examine how genes influence how drugs are metabolized and can inform individuals' responses to medication. The information gained from this study aims to help pave the way for future individualized dosing informed by each infant’s developmental and genetic characteristics. 

Working together will enable researchers at SickKids and CHU Sainte-Justine to study a range of medications used in critical care and a broader age range of patients due to the institutions’ distinct pharmacology expertise in both Neonatal ICU (SickKids) and Paediatric ICU (CHU Sainte-Justine). “All together, we are a new research team dedicated to optimizing drug dosing in critically ill children,” remarked Drs. Lewis and Thibault.  

Drs. Jacob Vorstman (SickKids) and Sébastien Jacquemont (CHU Sainte-Justine) will conduct a large-scale retrospective analysis to evaluate the presence of two or more conditions in patients that have variants associated with neurodevelopmental disorders. The study aims to identify the links between physical and psychiatric conditions to better understand the biology of mental and whole-body health relationships.

"This partnership offers a unique opportunity to investigate  data on a large scale within our two institutions," remarked Drs. Vorstman and Jacquemont. 

The collaborative multi-site study will leverage both institutions’ expertise in genomics, neuroscience and machine learning to develop the largest high-dimensional paediatric neuroimaging-whole-body-genomics dataset studied to date. It will also help inform how we safely, ethically and equitably work with existing data from electronic health records.  

This research study has the potential to transform how we diagnose, treat and understand psychiatric conditions and their interplay with overall health in children.  

Drs. Ashish Deshwar (SickKids) and Jean-François Soucy (CHU Sainte-Justine) will examine how RNA sequencing can be used to evaluate the impact of variations, thought of like spelling changes, on a child’s genetic code.

RNA sequencing, which examines how an individual’s body interprets their genetic code, is an important tool in diagnosing rare genetic conditions. Currently, the application of RNA sequencing is limited to genes that are expressed in clinically accessible tissues, excluding many children from benefiting from this technology. Using a gene-editing tool called CRISPR, this research study will induce the expression of any gene or instruction in cells from a patient to enable RNA sequencing and understand the impact of a particular spelling change. Lastly, research teams at SickKids and CHU Sainte-Justine will test therapies designed to correct RNA spelling changes. 

Drs. Deshwar and Soucy emphasized the potential of the study to advance precision medicine, commenting “if our project is successful, it will potentially enable us to provide a genetic diagnosis for children who otherwise would have gone undiagnosed. It will also develop a platform through which we can then test out certain types of emerging therapies targeted to individual genetic changes.” 

Drs. Andreas Schulze (SickKids) and Alexey V. Pshezhetsky (CHU Sainte-Justine) will use mouse modelling to examine the effects of combination therapies on Sanfilippo syndrome. Sanfilippo syndrome is a rare genetic condition where a change in a gene makes a child’s body unable to eliminate specific carbohydrates called glycosaminoglycans, which leads to serious problems in their brain and nervous system.

Building on previous Sanfilippo syndrome research, the study will examine new treatments that could potentially improve quality of life for children with Sanfilippo syndrome. If health improvement is detected in the animal model, it opens the door for future clinical trials and advancements for treating Sanfilippo syndrome and other rare genetic conditions.

“The medical scientific community is increasingly convinced of the effectiveness of these combined approaches,” say Drs. Pshezhetsky and Schulze. “We are confident that in the coming years a new therapeutic strategy will be developed for the benefit of children with Sanfilippo syndrome and their families.” 

Drs. Ian Scott (SickKids) and Rubén Marín-Juez (CHU Sainte-Justine) will create a system using zebrafish models with the ultimate goal of finding treatments tailored to each patient with congenital heart or vascular diseases. 

Congenital cardiovascular defects (CHDs) are the most common heart-related birth defects, often requiring multiple surgeries. Genetic variations linked to these conditions can impact the long-term health of a child, even leading to neurological alterations. Researchers will leverage zebrafish models to better understand these complex genetic diseases and identify personalized treatments in the lab. 

"Thanks to the commitment of the CHU Sainte-Justine Research Center and SickKids, a new era of bold and ambitious research is beginning," say Drs. Scott and Marín-Juez. "We are excited at the potential of creating patient-specific genetic models in the lab and conducting rapid testing of thousands of substances for precision therapies." 

Drs. Steven Schwartz (SickKids) and Michael Sauthier (CHU Sainte-Justine) will explore how machine learning (ML) and artificial intelligence (AI) can be used to rapidly analyze patient data and support clinical decision-making in paediatric intensive care units (PICUs).

By leveraging data from SickKids and CHU Sainte-Justine PICUs, the project, called Project AI2 (Ameliorate Incertitude by Artificial Intelligence), will develop a Clinical Decision Support System (CDSS) capable of analyzing vast patient data in real-time. This project will use AtriumDB, a secure data platform developed at SickKids, to gather information, analyze it using AI/ML, and provide quick insights to clinicians, which could help inform clinical decision-making in PICUs, with a goal of leading to better outcomes.  

Drs. Dilan Dissanayake (SickKids) and Fabien Touzot (CHU Sainte-Justine) will develop a biomarker-based scoring index to help identify patients who will benefit most from interleukin-1 beta (IL-1β) blocking medications to control inflammatory disease.

Childhood inflammatory diseases can cause serious irreversible damage to organs and severe medical complications. Many of these diseases involve unchecked inflammation driven by excessive secretion of a molecule called IL-1β. Early control of the inflammation produced by IL-1β is critical to altering the course of these diseases and preventing irreversible organ damage. Matching the right IL-1β blocking medication to the right patient at the right time is not always straightforward. Researchers will work to create an IL-1β index using cellular models and patient samples and use it as a guide or indicator to assist clinicians in making treatment decisions tailored to each patient's needs. 

“This collaboration provides us the opportunity to highlight an important truth — the sum of our knowledge together far exceeds our individual capabilities," say Drs. Dissanayake and Touzot. 

Drs. Mike Tyers (SickKids) and Sonia Cellot (CHU Sainte-Justine) will research miniprotein binders as a novel treatment for high-risk paediatric leukemias.

Patients with high-risk leukemia, especially those with acute myeloid leukemia (AML), have low survival rates despite treatment advances. There's an urgent need for new targeted therapies that can kill cancer cells while reducing risk of harm. Although antibodies have traditionally been used to target cancer-specific proteins, a new technology that can generate very small, high-affinity protein binders – termed miniproteins – that behave in much the same way as antibodies. Drs. Tyers and Cellot plan to develop miniproteins that specifically target biomarkers found only in cancer cells. Unlike antibody-based treatments, miniproteins can be developed more quickly and cost-effectively to target a broader range of cancer-associated proteins. This project aims to create and test miniproteins designed to treat paediatric AML and potentially other cancers, to pave the way for more precise and effective therapies.

“This collaboration allows us to leverage cutting-edge technology to identify and target therapeutic biomarkers in childhood leukemia and to offer personalized treatment based on the biology of cancer cells,” says Dr. Cellot.