Based in biology
We have a limited understanding of the biological mechanisms underlying neurodevelopmental disorders, limiting our choices of molecular targets for new treatments. In addition, some emerging biological mechanisms do not seem to be specific to any one diagnosis, but are common to multiple diagnostic labels, challenging their specificity. This heterogeneity within a population with the same diagnosis means that one subgroup may respond to a given treatment while the other will not. Therefore, we urgently need biomarkers and specific phenotypes to stratify patients into more homogeneous subgroups that will respond more uniformly to treatment rather than groupings predicted by existing nosological categories, which may or may not be based on underlying biology. To find these biomarkers of treatment response, individuals with neurodevelopmental disorders and age-matched controls are being assessed across a wide variety of research platforms. These provide comprehensive data on clinical, behavioural, and biological features of each participant so they can be more effectively categorized into a treatment response subgroup.
Below are the research platforms being used by POND for this comprehensive biological categorization of neurodevelopmental disorder subtypes:
Large genetic studies of individuals with neurodevelopmental disorders have shown that hundreds of genetic mutations contribute to these disorders, yet no single mutation account for more than 1-2% of cases. By taking advantage of recent advances in whole genome sequencing at The Centre for Applied Genomics, we can increase how many clinically-relevant genetic variants are identified and combine this with other biological markers of clinically-relevant subtypes across other platforms.
Epigenetics refers to changes in in gene expression that occur without changes in DNA sequence. This likely plays a role in neurodevelopmental disorders as mutations in in genes regulating gene expression (epigenes) often cause genetic syndromes associated with atypical neurodevelopment. Therefore, epigenetic alternations in individuals with neurodevelopmental disorders will be characterized as compared to controls and combined with clinically-relevant information from the other research platforms.
The greater amount of males with neurodevelopmental disorders, as well as the observation that abnormalities in certain hormonal systems have been associated with individuals with neurodevelopmental disorders motivates the collection of information about sex, gender and hormone levels to further characterize and categorize individuals with neurodevelopmental disorders.
Not only can altered immune function affect behavior, but it may also contribute to the biological processing underlying some neurodevelopmental disorders. By characterizing the levels of inflammatory and immunity mediators in the blood and combining this with information with other platforms (such as genetic and epigenetic platforms), this information can be used to further characterize and categorize individuals with neurodevelopmental disorders.
Imaging the brain using techniques like magnetic resonance imaging (MRI) and magnetoencephalography (MEG) provide pictures of the structure of the brain and information on the function of the brain. These characteristics include information on the genetics of the families combined with information from other research platforms to further characterize individuals with neurodevelopmental disorders. Our research has already shown the predictive value of this platform through observations such as the relationship between white matter connectivity and symptom severity, regardless of the clinical diagnosis.
Comprehensive characterization through clinical, behavioural and cognitive assessments allows for the biological markers and subtypes identified across other research platforms to be related to important functional, clinical and long-term outcomes of individuals with neurodevelopmental disorders.
Ontario Clinical Trials Network
POND developed the first clinical trials network dedicated to neurodevelopmental disorders. Importantly, the clinical trials network takes advantage of the rich information collected from POND participants across research platforms so unique biomarkers can be identified to separate responders from non-responders. By being able to associate treatment responders with markers of underlying biological processes rather than a specific neurodevelopmental disorder diagnosis, researchers have a better chance of identifying what subgroup(s) will respond to a given treatment. Furthermore, POND’s unique mouse modelling platform allows us to run parallel animal clinical trials alongside human clinical trials so that research questions that come up during clinical trials can be tested in real-time to further refine and improve clinical trial implementation, as well as understand why a certain subgroup might be responding more favorably to a given treatment. Similarly, POND’s cell modelling platform can be used to generate neural cell models from POND participants. This allows researchers to investigate the cellular characteristics associated with the individuals clinical, behavioural and underlying biological characteristics (as measured by the diverse research platforms), as well as use the cells for drug development, screening and testing.
Collaborative, data-driven research system
In order to effectively run these diverse platforms and networks, researchers and healthcare professionals from a variety of fields are part of the POND Network and work collaboratively, sharing their data through unique tools like Brain-CODE. Engineers, entrepreneurs, industry, community advocates, individuals with neurodevelopmental disorders and their families are also important parts of the POND Network. These individuals help to inform and refine the research process, as well as ensure the research findings can be converted into new tools, technologies and resources that can be applied in the clinic and the community setting to improve the lives of individuals with neurodevelopmental disorders.