Navigating the Future of Neurotherapeutics:
Insights from the ITN-TRIDENT Event
Authored by Latiyah Timothy
January 2024
In the fast-paced landscape of neuroscience and drug discovery, the ITN-TRIDENT event held on November 7-8, 2023 provided an incredible opportunity for collaboration and knowledge exchange/sharing. Hosted by the Initiative for Translational Neuroscience (ITN) and the Translational Initiative to De-Risk Neurotherapeutics (TRIDENT), this two-day event brought together brilliant minds to explore the theme, "How to Accelerate Drug Discovery in Neurodegenerative Disorders Through Public-Private Partnerships?" The event featured panel discussions and various research working meetings that showcased the latest advances and challenges in the field of neurodegeneration. The participants included researchers, clinicians, and industry representatives who shared their insights and perspectives on how to bridge the gap between basic science and clinical applications. The event also highlighted the importance of fostering multidisciplinary and cross-sectoral collaborations to accelerate the development of safe and effective therapies for neurodegenerative diseases such as Alzheimer's and Parkinson's. The ITN-TRIDENT event successfully provided a platform for engaging dialogue and knowledge exchange between the stakeholders of the neuroscience community. It also demonstrated the commitment and vision of ITN and TRIDENT to not only advance the translational neuroscience agenda but also improve the lives of millions of people affected by neurodegenerative diseases.
Day 1: Insights and Perspectives
The first day was a whirlwind of discussions, with multiple panel discussions providing attendees with a richer understanding of both the challenges and opportunities in neurotherapeutic research.
Panel 1: Improving Preclinical Models for Drug Discovery The discussions began with a focus on improving preclinical models of neurodegenerative diseases. There was a call to redefine our understanding of neurodegenerative diseases, with an emphasis on developing techniques that truly mirror the complexity of these disorders. Fostering collaboration between basic scientists and clinicians was encouraged by many attendees in the room, highlighting the critical need to bridge the translational gap from research to practice. In addition to using models with subtle phenotypes, the speakers also discussed the importance of incorporating genetic and environmental factors, biomarkers, and cognitive assessments into preclinical research. The goal was to create more realistic and predictive models that can inform the development of effective therapies for patients. The session was a stimulating and inspiring exchange of ideas and perspectives, reflecting both the diversity and innovation in the field.
Panel 2: Cognition as Translational Preclinical Biomarkers for Drug Discovery Cognition took centre stage in the second panel, where the discussions revolved around the challenges of assessing cognitive functions in neurodegenerative diseases. The use of touchscreens as a cutting edge tool for pre-clinical evaluation, similar to what is being used in the clinics in patients, sparked interest, considering the limitations of traditional methods. The dynamic conversation also touched upon the variability in human cognitive testing and the importance of robust biomarkers for effective translation from animal models to humans. The panelists highlighted the need for standardized and validated cognitive tests that can capture the subtle and complex changes in cognition that occur in different stages of neurodegeneration. The panel discussion concluded after exploring various promising directions for future research and clinical practice in the field of cognition and neurodegeneration.
Panel 3: Imaging as Translational Preclinical Biomarkers for Drug Discovery The third panel of the event discussed how imaging techniques can be used as preclinical biomarkers to bridge the gap between basic research and clinical applications. The panelists compared and contrasted the advantages and limitations of magnetic resonance imaging (MRI) and positron emission tomography (PET) in this context. They acknowledged that while PET is “KING”, MRI can provide high-resolution and non-invasive images of various biological processes, allowing for repeated measurements over time and across different disease stages as well as understanding pharmacodynamics. The main takeaway from the panel was that MRI requires standardization and robust protocols to ensure the reproducibility and validity of the results, especially when translating them from animal models to human trials.
Panel 4: Improving Public-Private Partnerships to Advance Drug Discovery The final panel of the day spotlighted successful public-private partnerships, showcasing examples like IVADO labs and the Allen Institute. The need for partners to be involved from the beginning of the research cycle with shared end goals, was a recurring theme. Industry insights provided valuable criteria for collaboration, emphasizing cross-validation of data, precise target identification, high efficacy of drug candidates, and a predictive model. The panelists also discussed the challenges and opportunities of working across multiple sectors, such as aligning incentives, managing expectations, and ensuring transparency. They highlighted the benefits of combining expertise, resources, and networks to accelerate innovation and impact. The panel concluded with some recommendations for future partnerships, such as fostering trust, communication, and feedback; leveraging existing platforms and infrastructures, and identifying common problems and solutions.
Day 2: Focus, Fun, and Future at the ITN-TRIDENT Working Meeting
The second day of the event provided a shift in focus with an emphasis on "Focus, Fun, and Future." Eight areas of core project research were presented, offering a deep dive into key aspects shaping the trajectory of neurotherapeutic development.
Cognition The first core research presentation highlighted the potential of touchscreens to drive the future of cognitive assessment. Traditional methods, like the Morris Water Maze, were critiqued for their lack of translatability. Touchscreens, with their global utility and robustness, emerged as a promising alternative. The discussion showcased tasks like PVD and VMCL for synucleinopathy and CPT for Alzheimer's, hinting at a paradigm shift in cognitive assessment techniques. In contrast to the Water Maze, which requires a large space and a complex setup, touchscreens are portable, scalable and adaptable to different species and environments. Moreover, touchscreen tasks can measure multiple cognitive domains, such as attention, memory, learning and executive function, with high sensitivity and specificity. Touchscreens can also provide rich data on response latency, accuracy and strategy, allowing for a deeper analysis of cognitive performance. Furthermore, touchscreen tasks are more engaging and rewarding for the animals, reducing stress and enhancing motivation. Touchscreens can also be integrated with other technologies, such as optogenetics, electrophysiology and imaging, to investigate the neural mechanisms underlying cognition. Therefore, touchscreens provide a novel, flexible, and powerful tool for cognitive assessment in preclinical research.
Marmosets The second core research presentation focused on the marmoset research program. The researchers explained that the marmosets were trained to perform cognitive tasks on touchscreen devices. The purpose of these tasks was to assess the marmosets' cognitive abilities and monitor any changes over time. In addition, the marmosets were injected with alpha-synuclein-preformed fibrils in the caudate & putamen, brain regions involved in movement and learning. The injection aimed to induce Parkinson's-like pathology in the marmosets, as alpha-synuclein is a protein that accumulates in the brains of Parkinson's patients. The researchers hoped to use the marmosets as a model to further study the mechanisms and progression of Parkinson's disease, and evaluate potential treatments.
Mice The third core research presentation unveiled humanized mouse models of synucleinopathy, recognizing the limitations of transgenic and first-generation models. Synucleinopathy is a group of neurodegenerative disorders characterized by the accumulation of alpha-synuclein protein aggregates in neurons and glia. These disorders include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Humanized mouse models aim to recapitulate the human pathology and genetics of synucleinopathy by introducing human alpha-synuclein genes or proteins into mice. The discussion highlighted the advantages and challenges of these models, as well as their potential applications for drug discovery and biomarker development. The discussion also presented ongoing characterizations of a humanized mouse model of Alzheimer's disease which included humanized APP, humanized Tau and humanized APOE 3/4. This model is expected to provide insights into the interactions and synergies between amyloid-beta, tau, and apolipoprotein E in Alzheimer's disease pathogenesis and progression.
Sex-Based Analysis+ The fourth core research presentation underscored the importance of sex-based analysis in research. Recognizing the impact of sex on study outcomes, participants discussed how accounting for it could enhance the reliability and relevance of findings, marking a step towards more inclusive research practices. They also highlighted the challenges and opportunities of implementing sex-based analysis in different disciplines and contexts, such as health, education, and social sciences. They emphasized the need for more awareness and training on sex-based analysis among researchers, funders, and policymakers, as well as the development of guidelines and tools to facilitate its application. They concluded that sex-based analysis is not only a matter of ethical and scientific rigour but also a way to foster innovation and societal change.
Open Science The fifth core research presentation focused on the topic of open science, which involves sharing data, methods, and results openly and transparently with the scientific community and the public. The participants discussed how platforms like TRIDENT and ITN enable and facilitate collaboration and open practices among researchers working on different aspects of drug discovery. They also debated the possible benefits and challenges of open science for innovation, especially in overcoming the "Valley of Death" that often prevents promising discoveries from reaching clinical trials and patients.
Imaging and Data Capture: Advancements and Challenges The next core research presentation focused on imaging and data capture, highlighting advancements in Awake MRI studies. Recognizing the impact of repeated anesthesia on cognitive decline in longitudinal studies prompted a shift in approaches. The Rodent Automated Bold Improvement of EPI Sequences (RABIES) pipeline was also spotlighted, offering a standardized image processing and data quality platform for rodent fMRI. This presentation also identified how Awake MRI studies can provide more accurate and reliable data on brain activity and connectivity. One of the novel features of Awake MRI studies is the ability to use touchscreen devices to test the cognitive and behavioural functions of rodents during the scanning session. The various benefits of RABIES were presented, such as improved signal-to-noise ratio, reduced motion artifacts, and enhanced reproducibility across different scanners and sites.
iPSCs and Molecular One of the topics of discussion was the application of iPSCs to model neurodegenerative diseases in vitro. iPSCs are adult cells that have been reprogrammed to an embryonic-like state and can differentiate into various cell types, including neurons. By using iPSCs derived from patients with neurological disorders, researchers can create cellular models that recapitulate key aspects of the disease process. Several speakers presented their work on developing and optimizing iPSC-based assays to measure neuronal toxicity, survival, and function in response to different stimuli. They also discussed how iPSC models can help elucidate the molecular mechanisms underlying neurodegeneration and identify potential therapeutic targets. Another topic of interest was the use of advanced imaging techniques to visualize and quantify the molecular and structural changes that occur in the brain during neurodegeneration. Participants shared their insights on how to correlate pathological findings with cognitive and behavioral outcomes, as well as with MRI data. They also highlighted the advantages of using light sheet microscopy, a novel method that allows high-resolution imaging of large tissue samples with minimal damage. The ITN-TRIDENT event was a remarkable event that demonstrated the power of collaboration, research innovation, and knowledge sharing in the field of neurotherapeutics. The participants engaged in many lively and insightful discussions on various topics of research, ranging from cognitive assessments to imaging advancements and molecular explorations. The event revealed a strong commitment to advancing the field of drug discovery and finding new solutions for neurodegenerative disorders. The collaborative spirit, diverse perspectives, and shared dedication that were observed during the event undoubtedly built a solid foundation for brain research. The ITN-TRIDENT event inspired numerous engaging discussions and networking opportunities, supporting the need to continually work toward a future where the power of collaboration and scientific innovation are leveraged to unravel the mysteries of the brain.