BC Children’s Hospital Research Institute – Page 3

The use of human stem cells to understand mechanisms and develop treatments for neurological disorders

Brain disorders are among the most significant health problems of modern day with enormous medical, social and economic burdens in British Columbia, Canada and globally. There is a substantial gap between the burden of brain disorders and the resources available to treat them. Neurodevelopmental disorders are particularly devastating, placing a heavy emotional and economic burden on children and their families. A major challenge in tackling these disorders is the inability to obtain and study brain cells directly. New technologies which allow stem cells to be transformed into brain cells are starting to help overcome this hurdle.

By studying brain cells derived from human stem cells, Dr. Pouladi aims to

understand how brain disorders develop and
to identify new ways to treat them. A major focus of his studies are monogenic neurological disorders and in particular fragile X syndrome (FXS). FXS is the most common inherited form of intellectual disability and remains without effective treatments options.

The stem cell-based discovery platform established and knowledge gained as part of Dr. Pouladi's program have the potential to advance therapeutic development for not only FXS, but also other neurodevelopmental disorders.

Optimizing post-procedural pain trajectories through patient-oriented research and artificial intelligence

Our goal is to use smartphones and artificial intelligence to improve pain management for children having surgery. This is needed because many children still have a lot of pain even a year after surgery. The pain affects their daily life, and might cause them to return to hospital. A child’s pain is affected by many things, like their biological sex, anxiety, coping skills, pain level, and type of surgery. Importantly, some of these can be altered.

We will collect data to identify patterns that predict which children

do well after surgery, so we can learn from them or
do not do well/have significant pain, so we can help sooner or even prevent it. We will involve families and children having surgery now, to collect data for a pain risk score to help future children.

We will design a tool to share pain risk data with families and doctors and test these tools in children coming to hospital for spine, tonsil or dental surgery. We hope that using these tools (pain prediction models) will improve the child’s individual care. Identifying children at high pain risk will allow us to intervene before their surgery. This will lead to quicker recovery, less time in hospital, and less chance of addiction to painkillers (opioids).

COVID-19 in children and young adults in BC – evaluation of public health measures and epidemiologic support for decision-makers

We do not know how many children and young adults have been infected with COVID-19 because they have milder symptoms and are usually not tested. For most infections children and young adults are important in spreading the infection. We urgently need to find out how much children and young adults have had the COVID-19 virus. The only way to do this is by testing a large number across the population. In this project we will collect saliva and blood from 6,000 people under 25 years and test for the COVID-19 virus and antibodies against the virus. We will send kits for people to collect these samples at home and then mail them to us. We will then know how many children and young adults have been infected, which will help make decisions about physical distancing and school closures.

Novel nanomedicines for resolving inflammation as a treatment for type 2 diabetes

This project proposes a new nanomedicine approach to treat type 2 diabetes (T2D). Studies in humans and mice have shown that inflammation in fat tissues and the pancreas is a major driving force for the development of obesity-induced insulin resistance and diabetes. A major limitation of current drugs is that they distribute over the entire body, exposing all cell types, while only a small amount reaches the desired target cells at disease sites, such as macrophages in inflamed tissues. This results in limited drug efficacy and unwanted side-effects. We aim to develop a new treatment for T2D that exploits the natural physiological processes to suppress inflammation in macrophages within fat tissues and the pancreas with high potency. We will use lipid nanoparticles (LNP), which are drug delivery systems customized to stably carry a large amount of drugs to macrophages.

Scientific development in this project will involve testing of LNP containing immune-modulating drugs in obese, diabetic mice, and measuring the anti-inflammatory and anti-diabetic effects. With close to half a billion people worldwide suffering from T2D, we believe that the proposed cell-specific treatment can have a significant impact on health and the economy.

Role of the Histone Acetyltransferases p300/CBP in Brown Adipose Tissue Adaptive Thermogenesis

Obesity is rising in Canada at an alarming rate, which is bad for our healthcare system because it results in diseases like heart attacks and diabetes. Although eating less and exercising more can reduce weight, these lifestyle changes can be difficult to maintain, prompting interest in finding ways to ramp up the calorie-burning processes in the body to promote weight loss. Brown adipose tissue (BAT) is a kind of fat that is found in both humans and mice. Unlike white adipose tissue, BAT is specialized for calorie burning rather than storage. We don't know exactly how the body controls how much BAT it makes, how it turns BAT on for burning energy to control body weight, or why some people lose their BAT with age.

One possible way these processes might be controlled is via proteins that 'open' and 'close' DNA within BAT to turn key calorie-burning genes on and off. Proteins that close DNA within BAT can worsen obesity by blocking BAT development, so the body can't burn as many calories. We are interested in how proteins that 'open' DNA (specifically, a pair called p300 and CBP) in BAT can influence energy expenditure.

To find out whether p300/CBP activate BAT calorie burning, we will induce obesity in mice that have p300/CBP working within their BAT, and in mice without these proteins. We expect mice missing p300/CBP will also have problems making BAT, so they will also be unable to burn energy using this tissue – resulting in the development of obesity and diabetes.

Development of a novel intranasal oligonucleotide delivery approach for Huntington disease

Huntington disease (HD) is a progressive brain disorder affecting movement, mood, and cognitive skills, caused by inheriting a mutated copy of the huntingtin gene. This results in the production of a mutant huntingtin protein (mHTT) that is toxic to critical nerve cells in the brain. Reducing mHTT using specialized pieces of DNA, called antisense oligonucleotides (ASOs), should slow or prevent disease onset. However, ASOs cannot reach the brain when delivered into the bloodstream, due to the presence of the blood-brain barrier (BBB), and thus require surgical injection into the brain or the cerebrospinal fluid (CSF) that bathes the brain.

Intranasal administration is a delivery method that bypasses the BBB and can deliver large therapeutic molecules to the brain. Here, we propose a strategy to deliver ASOs to the brain using nanoparticle (NP) carriers we have developed which encapsulate ASOs, enhance their ability to cross cells membranes and penetrate the BBB. We will intranasally deliver these ASO NPs in HD mice to reduce mHTT in the brain. This approach represents a novel non-invasive means for improving delivery and distribution of ASOs into the brain, and advancing development of HD therapies.

Findings will be shared with the scientific public through publications and conference presentations, and to the general public and HD patients through educational seminars/workshops in our lab.

Therapeutic efficacy of a novel enteral nutrition strategy in pediatric inflammatory bowel disease

Inflammatory bowel disease (IBD) is characterized by chronic, relapsing inflammation of the gastrointestinal tract, and includes Crohn’s disease (CD) and ulcerative colitis (UC).

The gold standard induction therapy for treating active pediatric CD is “exclusive enteral nutrition” (EEN), which is a nutritionally complete liquid diet provided by tube feeding that excludes normal food intake. This nutritional strategy is superior to standard induction therapies; however, treatment must be maintained for 6-12 weeks to induce remission, and relapse rates are high after stopping EEN.

To date, EEN in pediatric patients with UC has not been shown to be effective and as a result is not regularly used. Also, the standard enteral formula does not contain fibre and is low in vitamin D, even though both factors lead to beneficial changes in gut bacteria and reduce inflammation in IBD.

Dr. Healey will recruit pediatric CD and UC patients to determine if enteral formula with fibre and concurrent oral vitamin D3 improves IBD beyond standard EEN and medications. Her research will also include undertaking animal studies to explore the mechanisms of this novel EEN strategy. The results of this research could lead to improved treatment strategies and outcomes for children with IBD.

Determining best practices in CBT implementation for pediatric OCD

Youth with obsessive compulsive disorder (OCD) often experience distressing experiences (for example, unwanted thoughts) which they try to prevent or relieve through obsessive strategies such as repeated hand-washing. Without treatment, OCD tends to remain a problem for youth and makes their lives very difficult.

Cognitive behavioral therapy (CBT) has been shown to reduce symptoms and improve quality of life for most youth with OCD. However, CBT is a broad term that can include different strategies and exactly which strategies are the best to use has not been carefully studied.

Dr. Selles’ research will involve implementing a five-day intensive CBT program for youth with OCD, comparing two different strategies for youth and two different strategies for therapist involvement. This study will examine how well the treatment works and compare the impact of these strategies on symptoms, child and family wellness, family preference, and cost.

This research will help bring a needed clinic service to British Columbia while providing therapists with clearer ideas about how to provide treatment in a way that will benefit youth with OCD the most.

Silent genomes: Reducing health care disparities and improving diagnostic success for children with genetic diseases from Indigenous populations

Health Research BC is providing match funds for this research project, which is funded by the Genome Canada/CIHR Large-Scale Applied Research Project (LSARP): Genomics and Precision Health funding opportunity. Additional support is provided by Genome BC, the BC Children’s Hospital Foundation, BC Provincial Services Health Authority and the University of British Columbia (UBC).

Indigenous populations in Canada and around the world face unique health challenges, inequities, and barriers to healthcare. As a result, they typically have poorer health outcomes than non-Indigenous groups.

The health disparity gap widens when it comes to Indigenous populations’ access to the technology and research involved in genomics – the study of the complete set of human genes – which have advanced health care by allowing medical treatments to be tailored to the specific needs of individual patients through precision medicine, routinely available to other Canadians.

Dr. Laura Arbour, a clinical geneticist at BC Children’s Hospital and Island Health, and a professor in UBC’s Department of Medical Genetics, is working to address the growing genomic divide – particularly the lack of background genetic variation data for Indigenous populations – through the Silent Genomes project. The four-year project aims to improve health outcomes by reducing health disparities, enhancing equitable access to diagnosis, treatment, and care for Indigenous children with genetic diseases. Arbour is joined on the project by the University of Northern British Columbia’s Dr. Nadine Caron, and Dr. Wyeth Wasserman from UBC and the BC Children’s Hospital Research Institute, where the research will be conducted, along with BC Women’s Hospital + Health Centre.

The Silent Genomes research team will work with First Nations, Inuit and Métis partners across Canada to establish processes for Indigenous-led governance of biological samples and genome data, leading to policy guidelines and best practice models for genomic research and clinical care.

The project will also create an Indigenous Background Variant Library (IBVL) of genetic variation from a pool of 1,500 First Nations Canadians that will improve the accuracy of genomic diagnosis by providing necessary reference data for Indigenous populations living in Canada and globally. Researchers will also assess the effectiveness of the IBVL to lower health care costs, and plan for long-term use of the IBVL for Canadian Indigenous children and adults needing genetic/genomic health care.

End of Award Update – July 2024

Results:

The Silent Genomes Project (SGP) successfully achieved four main objectives:

Established Indigenous-informed policies for Indigenous governance over biological data through the S-GIRDD Steering Committee.
Developed a comprehensive Background Variant Library (IBVL) using genomic data from First Nations participants, that was operational in January 2024, allowing internal testing with potential for expansion with more genomes from Indigenous participants.
Conducted whole genome sequencing for Indigenous patients with suspected genetic diseases, with standard analysis completed for 89 patients/families and ongoing analysis for unresolved cases.
Provided research training for Indigenous students in precision diagnosis and health economics over a six-year period. With the scholarship support of Life labs, the project team ensured the participation of over 30 students in the first 5 SING Canada workshops.

Impact:

Governance within the Silent Genomes Project ensured development of policies and operational guidelines for Indigenous involvement in genomic research. The Silent Genomes Indigenous Rare Disease Diagnosis Steering Committee has developed the processes for variant release which were implemented for the IBVL, protocols for clinical research applications planning to use the IBVL, and review process for the manuscripts where IBVL was used for the variant selection. The process of transformation of the advisory S-GIRDD Steering Committee into the sustainable IBVL Governance Committee is underway. The project leadership and the S-GIRDD committee members participated in the 2nd “DNA on Loan” conference organized by CIHR, where gaps in currently existing guidelines, that the team was exposed through the SG lifetime, have been discussed. Internationally, utilizing the mechanism approved by the S-GIRDD (online restricted access to frequency of Indigenous variants) within accepted upon ethical frameworks (CARE principles), was reviewed and is under consideration by two other jurisdictions (Australia and New Zealand).
Efforts were made to enhance the capacity of healthcare providers, Indigenous patients, communities, and students to engage with genomics research and health care. Five SING Canada workshops were conducted by Dr. Tall bear and her team, with the support of SG team members. Additionally, two Indigenous graduate students have either completed or are nearing completion of their studies. Educational materials developed by Activity 1 are available on the Silent Genomes website, along with regularly updated content on Genetics and Genomics research best practices.
The first release of the Indigenous Background Variant Library (IBVL) is undergoing testing and will be available for clinical use within the next few months. Once completed, this effort will enable assessment of how genomic variant knowledge impacts diagnostic clarity for Indigenous patients with rare diseases. The SGIRDD Steering Committee is actively involved in developing sustainable IBVL usage processes beyond the project’s duration. Internationally, the pipeline and user interface developed within the project have been shared with the Varoomed Project (Aotearoa/New Zealand), for testing or partial adoption.
Aims to increase access to genetically based diagnoses and care involved closing enrollment and engaging National Clinical Network (NCN) teams across 11 Canadian sites, with ongoing discussions to address limitations in Canadian TCPS2 Chapter 9 guidelines. Efforts were made to raise awareness among healthcare providers regarding barriers to accessing clinical and research genomics post-project. The Culturally Informed Genetic Counselling Guide, provided to each site, has been published on the SG Best Practices website for wider dissemination. The NCN continues to work on breaking down barriers to access to clinical and research genomics.

Potential Influence:

The lessons learned while establishing a National Clinical Network will be used to break down barriers in access to clinical and research genomics for Indigenous peoples.
Further collaborations are needed to fill the existing gaps in policies and guidelines related to Indigenous involvement in genomic research.
The S-GIRDD Steering Committee is currently focused on developing processes for sustainable use of the IBVL beyond the Silent Genomes project, with the goal of independent continuous seamless governance and technical support during the lifetime of the IBVL.
The international “Be FAIR and CARE” meeting gathered international Indigenous Genomics specialists from around the world, which conceived an idea of creating an International Indigenous Genomics Advisory and Research Consortium which would provide the necessary skills and knowledge for the development of stipulations for Indigenous data sharing processes globally. If similar projects are using comparable pipelines and user interface (e.g. the ones developed within the project), it may technically ease global data sharing processes.
The Health Economics study developed a set of practical and collaborative approaches for qualitative research when working with Indigenous People and communities to provide opportunities to advance Indigenous governance, capacity, and equity approaches.

Next Steps:

Building upon the original SGP, the new extended work is intended to catalyze longer-term efforts that could be sustained under healthcare systems (as the reference data provided by the IBVL becomes standard of care for diagnostic testing), funded by grants such as an anticipated Genome Canada health competition, directly supported through federal allocation, or a mixture of these models. Over the next 5 years, there are four key foci. First, developing sustained funding for the IBVL as an integrated reference data source for clinical diagnosis of rare disease. Second, achieving broader inclusion of Indigenous communities in the IBVL to enable the reference data to be of equitable utility for all Indigenous peoples of Canada. Third, to build upon emerging capacity to substantially increase the number of Indigenous researchers, research leaders, and genetic/genomic health care providers. Fourth, to identify and develop new health-related applications requiring reference data that are of priority to Indigenous peoples.

CHILD-BRIGHT: Child Health Initiatives Limiting Disability – Brain Research Improving Growth and Health Trajectories

Health Research BC is providing match funds for this research project, which is funded by the Canadian Institutes of Health Research’s (CIHR) Strategy for Patient-Oriented Research (SPOR) Networks in Chronic Disease.

As many as 850,000 children in Canada are living with a brain-based developmental disability (BDD). They face lifelong challenges with mobility, language, learning, socialization and self-care, which impacts their quality of life and create special challenges for their families. They also typically have poorer health, lower educational achievement, fewer economic opportunities and higher rates of poverty than children without disabilities.

CHILD-BRIGHT is a pan-Canadian network of clinicians, patients, families and scientists committed to making the future brighter for infants, children and youth with lifelong brain-based developmental disabilities and their families. The five-year project focuses on those diagnosed with a brain-based disorder such as autism, cerebral palsy, fetal alcohol spectrum disorder, learning or intellectual disabilities, as well as those at high risk for a brain-based developmental disability due to pre-term delivery, congenital heart disease, or genetic anomalies.

Dr. Dan Goldowitz, a professor of Medical Genetics at UBC and the Centre for Molecular Medicine and Therapeutics at the BC Children’s Hospital Research Institute, is one of CHILD-BRIGHT’s three co-directors, along with Drs. Steven Miller at University of Toronto/The Hospital for Sick Children (SickKids), and Network Director Annette Majnemer of McGill University Health Centre’s Research Institute.

CHILD-BRIGHT’S 12 patient-oriented research projects fall under three themes: “Bright Beginnings” – innovative early therapies to optimize brain and developmental outcomes; “Bright Supports” – integrating mental health and wellness support into care for children and youth, and “Bright Futures” – re-designing key parts of health care services to be more responsive to family needs, throughout the trajectory of the child’s and the family’s development.

Goldowitz is overseeing the network’s training program. His UBC team will engage with patients, researchers and policy-makers to foster a culture of patient-oriented research that could help serve as a model for future health research and lead to better outcomes for patients and their families.

End of Award Update: May 2022

Results

Training Program – CHILD-BRIGHT’s Training Program has worked to develop capacity in patient-oriented research (POR) to ensure that authentic patient-partner engagement is fundamental to the research process. To this end, regular training offerings such as webinars, workshops, and self-directed modules, have been critical. However, initiatives that strive towards changing the research culture around POR will have a far lasting impact. For instance, the Summer Studentship Training Program exposes undergraduate students to the core tenets of POR while providing opportunities to gain practical experience within a CHILDBRIGHT research project. Funding initiatives such as the “Graduate Student Fellowship in POR” provides support to graduate trainees or postdoctoral fellows to augment a research project to involve the patient-partner voice. Together, outputs like this help create capacity for POR in tomorrow’s research leaders.

Parent-EPIQ – In the Parent-EPIQ studies, we found that we need to revise how we talk about the futures of children born very preterm. Parents want a broader perspective with positive and negative outcomes including functioning, quality of life and family wellbeing. We also successfully implemented interventions to improve language abilities in children born preterm using the proven EPIQ quality improvement technique with parent involvement. Lastly, we provided up to date Canadian information for parents and health care providers in four annual reports.

IMAGINE – This project has determined that approximately half of children affected with symptoms of atypical cerebral palsy can be provided with a genetic diagnosis when trio whole genome sequencing is used. We also determined that trio whole genome sequencing is superior in diagnostic power to the currently used clinical exome sequencing. Bioinformatics pipelines were created to optimize diagnoses via these whole genome methods. These have been presented and published or are in press. Several patient-facing tools were developed for this project, in conjunction with parent-partners associated with the project. All were well accepted and appreciated, which supports the advantages of parent partner involvement.

PIUO – Many infants, children and youth with rare diseases and complex conditions affecting the central nervous system often experience pain and irritability. Sometimes the pain is due to medical procedures such as scoliosis repairs, or due to chronic conditions such as muscle spasms. There are, however, many times when it is difficult to find a source as these children often have severe language delays. Engaging clinicians in assessing and treating PIUO using history, physical examinations, diagnostic tests, and screens to rule out unknown causes of indeterminate pain has influenced the way this issue is being treated clinically. The pathway also provides support and guidance for parents of these children.

Impact

Parent-EPIQ – As a result of the Parent-EPIQ project, our work has highlighted what parents view as important: functioning, quality of life and family well-being. These areas are not currently captured in data collection as part of the Canadian Neonatal Follow Up Network. This major impact of work has been taking steps to shift the paradigm of reported outcomes in neonatal follow up research using these findings through changes to our annual report and data collection, implementing recommendations from parents of preterm children, and considering parent perspectives when reviewing and evaluating data requests and future research.

IMAGINE – The results of this project have provided a diagnosis to families who previously had no etiology for their child or children’s problems. This has provided an explanation for these families, and in many cases genetic counseling has provided information on the trajectory of the illness, risk to other family members and to future pregnancies. An understanding of etiology enables treatment options to be considered. One of the patient-facing tools, the Genomic Results Booklet, has been tested in clinical usage in the BC Children’s Hospital Pediatric Neurology. This clinic has seen the importance and advantages of providing post-testing information in this format. A research paper is currently under development that describes the impact of this tool in clinical use.

PIUO – Many infants, children and youth with rare diseases and complex conditions affecting the central nervous system often experience pain and irritability. Sometimes the pain is due to medical procedures such as scoliosis repairs, or due to chronic conditions such as muscle spasms. There are, however, many times when it is difficult to find a source as these children often have severe language delays. Engaging clinicians in assessing and treating PIUO using history, physical examinations, diagnostic tests and screens to rule out unknown causes of indeterminate pain has influenced the way this issue is being treated clinically. The pathway also provides support and guidance for parents of these children.

Potential Influence

Parent-EPIQ – We have leveraged powerful partnerships with parents and collaborations with advocacy groups to co-create resources and materials that directly reach families. Not only have we been able to disseminate our research findings through traditional academic publications, but we have pursued innovative and novel avenues to benefit more families and more children born preterm which is the ultimate objective of our work. Our research is being noticed. PI Dr. Synnes was invited to present results in Seoul, Korea and virtually to Boston Children’s Hospital in the fall of 2023.

IMAGINE – This project has provided evidence for the efficacy of the diagnostic and clinical care used: (1) approach of whole genome sequencing (2) bioinformatics pipeline, and (3) has demonstrated the advantages of parent involvement throughout. We hope that the presentations and academic papers produced will provide a framework for best practices for similar families.

PIUO – Our co-investigators were invited to speak in Prince George’s Northern University Hospital, and locally in several outreach clinics and hospital rounds about our pain pathway protocol. Our wider impact via the academic literature remains to be determined as we await statistical analysis for write up in research journals.

Next Steps

Parent-EPIQ – In this work, we have identified specific assessment tools to measure parent-identified outcomes. Future research will involve the feasibility of implementing these tools into routine data collection as part of the Canadian Neonatal Follow Up Network. The next steps will include leveraging the success of the CHILD-BRIGHT Phase 1 Parent-EPIQ project to start work on the CHILD-BRIGHT Phase 2 project: “Implementing Patient-Reported Outcome Measures (PROMs) in follow-up care of preterm children using a hybrid implementation-effectiveness design”.

IMAGINE – Our next steps include efforts towards knowledge mobilization and implementation science to identify how best to integrate what we have learned in this study into clinical practice. Future research will continue to finesse bioinformatics methods and re-examination of as-yet undiagnosed children. We are working on challenging variants that include complex sequence repeats and rearrangements.

PIUO – Our next steps will be to complete data analysis and use the results to inform an implementation science project as part of CHILD-BRIGHT Phase 2, which will allow our team to expand the pain pathway to pediatricians across BC.