Shared Biology Across Disorders
We have a limited understanding of the biological mechanisms underlying neurodevelopmental disorders. Some biological mechanisms are only seen in some individuals with the same diagnostic label. Other biological mechanisms are common across multiple diagnostic labels. POND is researching these similarities and differences across disorders. POND uses many types of tools and methods in this research. These are broadly categorized into research platforms. Individuals with neurodevelopmental disorders and age-matched controls are being assessed across these platforms. These provide comprehensive data on the clinical, behavioural and biological features of each participant. This data will advance our understanding of neurodevelopmental disorders and the underlying biology. POND is also using this data to discover individualized treatments based on a person’s biology.
Ontario Clinical Trials Network
POND developed the first clinical trials network dedicated to neurodevelopmental disorders in Canada. Trial participants are assessed across the POND research platforms. This provides a unique opportunity to understand why some trial participants respond to a treatment while others do not. These two groups may have distinct biologies. The clinical, behavioural and biological data from participants can be searched to identify these unique biological markers (biomarkers) of treatment response. A key goal for POND is to identify clinically relevant subgroups based on these biomarkers. These biomarkers may allow us to people with the best treatment for them.
This is a more precise approach compared to many previous clinical trials. Previous trials would often focus on treating a specific neurodevelopmental disorder diagnosis. We are now learning that the underlying biological mechanism can be different in people with the same diagnosis. Thus, any particular therapy might only be effective in a subgroup of trial participants. These trials often failed, showing varied treatment responses. If we target individuals with the same biomarkers, treatment response should be more consistent. Clinically relevant subgroups based on POND’s biomarkers have a better chance of responding to a given treatment.
This approach powerfully integrates basic and clinical research with treatment development. The goal is to give healthcare providers information they need to be more precise in choosing treatments. Selecting treatments based on a person’s underlying biology should lead to more effective and efficient care.
Lead: Evdokia Anagnostou
Investigators: Olaf Krauss De Camargo, Rob Nicolson, Muhammad Ayub, Russell Schachar, Jennifer Crosbie
Diverse Research Platforms to Characterize Biology
Below are short descriptions of each research area. Each platform uses different methods to provide information on a participant and their disorder. Together, they provide comprehensive data on clinical, behavioural and biological features. This linked information allows us to further characterize and categorize individuals with neurodevelopmental disorders.
Large studies have shown that hundreds of genetic mutations contribute to neurodevelopmental disorders. However, no single mutation accounts for more than 1-2% of cases. Available technologies limit our ability to identify these genetic mutations. Recent advances in whole-genome sequencing have doubled the identification of clinically relevant genetic variants. The application of this state-of-the-art technology in POND builds on our earlier studies. Combining whole-genome sequencing with data from other platforms can help to characterize the underlying biology of neurodevelopmental disorders.
Platform Lead: Stephen W. Scherer
Platform Investigators: Christian Marshall, Evdokia Anagnostou, Rob Nicolson, Paul Arnold, Russell Schachar, Peter Szatmari, Stelios Georgiades, Xudong Liu
Children and youth can share similar functional needs despite having different neurodevelopmental disorders. We believe that effective treatments should target behaviours and cognitive traits shared across diagnostic labels. POND uses clinical, behavioural and cognitive assessments. This measures important functional, clinical and long-term outcomes. Biological data collected through other research platforms provide the context of underlying mechanisms contributing to these traits. Understanding the relationship between behavioural traits and biological mechanisms can help us understand these disorders. It can also help to identify clinically relevant subtypes of neurodevelopmental disorders. These subtypes can help inform treatment options more tailored to the unique person.
Platform Leads: Russell Schachar, Jennifer Crosbie, Elizabeth Kelley
Platform Investigators: Evdokia Anagnostou, Jessica Brian, Deryk Beal, Stelios Georgiades, Noam Soreni, Rob Nicolson, Ryan Stevenson, Paul Arnold, Alice Charach, Peter Szatmari
Many different factors may lead to a neurodevelopmental disorder. Only some individuals with a neurodevelopmental disorder have a known genetic cause, while others do not. Epigenetics can help to fill this knowledge gap. Epigenetics refers to mechanisms that modify DNA and proteins affecting its shape. These modifications regulate gene expression in cells without changing the primary DNA sequence. A group of genes known as epigenes regulates gene expression through these mechanisms. Epigenes drive normal development by programming unique patterns of modifications in each cell type in the body. Such modifications can be altered by mutations in epigenes or by environmental factors such as diet or drugs. Mutations in epigenes have been associated with altered neurodevelopment. For example, these mutations have been found in people with intellectual disabilities or autism. Epigenetic alterations can be measured by the extent of DNA methylation on different genes. Characterizing DNA methylation in disorders can help us understand what causes them. The patterns of DNA methylation also provide unique biological signatures. These signatures can be combined with data from other research platforms to help define clinically relevant subtypes of neurodevelopmental disorders. These epigenetic alterations may also help to identify new therapeutic targets.
Platform Lead: Rosanna Weksberg
Platform Investigators: Paul Arnold, Evdokia Anagnostou, Russell Schachar
Altered immune function can affect behaviour. It may also contribute to the biological processing underlying some neurodevelopmental disorders. POND Network scientists believe that subsets of people with neurodevelopmental disorders have these alterations. It likely relates to the wide variety of potential causes of neurodevelopmental disorders. We are characterizing the profiles of immune cells and levels of inflammatory mediators in blood samples from participants. Our results will help us understand the biology underlying differences in symptoms and behaviours in neurodevelopmental disorders. These results will be combined with data from other research platforms to help define clinically relevant subtypes of neurodevelopmental disorders. It may also facilitate the development of new treatments.
Platform Leads: Rosanna Weksberg, Jane Foster, Dawn Bowdish
Platform Investigators: Evdokia Anagnostou, Eyal Grunebaum, Russell Schachar, Stephen Scherer, Stelios Georgiades, Rob Nicolson, Xudong Liu
Neurodevelopmental disorders are characterized by different clinical, behavioural and cognitive traits. These traits relate to changes in the structure and/or function of the brain. Three-dimensional pictures of the brain’s structure can be developed using techniques like magnetic resonance imaging (MRI) and magnetoencephalography (MEG). These techniques provide information on the structure and function of the brain. This information can be combined with data from other research platforms to help identify clinically relevant subtypes.
Platform Lead: Jason Lerch
Platform Investigators: Margot Taylor, Elizabeth Pang, Russell Schachar, Evdokia Anagnostou, Stephanie Ameis, Meng-Chuan Lai, Rob Nicolson
Sex and Gender Influences
Most neurodevelopmental disorders are more common in males than in females. This reflects both sex- and gender-related influences in developing these conditions. There is also a possible gender-based diagnostic bias. We are researching how neurodevelopmental disorders present in different sexes and genders. We also want to understand how these sex and gender-related influences are associated with typical sex and gender similarities and differences. Individuals with neurodevelopmental disorders may also show atypical characteristics in certain hormonal systems, such as growth, stress-response and sex-related endocrinological factors. In our research, we collect information on sex, gender and hormone levels from people with neurodevelopmental disorders and controls. With this information, we can examine how these factors affect screening, diagnosis, concurrent health issues, etiology and treatment. This research helps us understand risk and protective mechanisms in individuals with neurodevelopmental conditions. It can also be combined with data from other research platforms to help identify clinically relevant subtypes of neurodevelopmental disorders and better tailor treatment.
Platform Leads: Mark Palmert, Meng-Chuan Lai
Platform Investigators: Evdokia Anagnostou, Jason Lerch, Peter Szatmari
The causes of neurodevelopmental disorders are highly diverse. No single genetic or environmental factors account for more than a few percents of cases. In fact, many cases are attributed to a collection of factors. In mouse models, we can look at the impact of specific genetic changes, environmental manipulations and their interaction within well-controlled experiments. We can also look at this collection of models as reflecting the mix of neurodevelopmental disorder biologies seen in the clinic. Behavioural and brain imaging data can produce large amounts of data on these factors and their interactions. A unique feature of this platform is that we can run parallel animal clinical trials alongside human clinical trials. We can test research questions that come up during clinical trials in real-time. It can also help us to understand why a certain subgroup might be responding better to a given treatment. Thus, research conducted in mouse models can help in understanding the biology of neurodevelopmental disorders. It also adds to the rigour and success of clinical trials.
Platform Leads: Jason Lerch, Jane Foster
Platform Investigators: Mark Henkelman, Mark Palmert, Karun Singh, Nathalie Berube, James Eubanks
A difficulty in applying scientific findings from the lab into clinical care can be differences in biology. Cell models created in animals are often less variable and less complicated than human biology it is trying to model. POND’s cell modelling platform is narrowing this gap. The platform can generate neural cell models from blood samples of POND participants. This allows researchers to associate cellular characteristics with participant data. Biomarkers from clinical, behavioural and biological measures can be associated with cellular characteristics. Cell models can be used for drug development, screening and testing. Research findings can be applied in clinical trials to understand variable treatment responses and test treatment modifications.
Platform Leads: James Ellis, Karun Singh
Platform Investigators: James Ellis, Mick Bhatia
Our brains and bodies change and develop over time. As a result, neurodevelopmental disorders will have different effects on a person’s brain and body across their lifetime. Thus, we are measuring the behaviour, cognition and biology of the same individuals over time. In addition, different biologies are associated with different trajectories of these disorders. Understanding the different trajectories of individuals with the neurodevelopmental disorder may allow us to identify different clinically relevant subtypes and predict treatment outcomes.