The first MAPTA (Modeling Alliance of Systems Pharmacology in TAuopathies) Workshop held on May 26, 2017 in Washington, D.C. brought together key thought leaders and computational modeling experts from academia and industry to advance tauopathy research for TBI and other neurodegenerative disorders.

The microtubule associated-protein tau is a key driver of neurodegeneration in Alzheimer’s disease and other neuropathologies, such as Traumatic Brain Injury (TBI), which have few or no treatment options. Despite thousands of preclinical studies published on tau, few therapeutic trials have been conducted due to the complexity of the target.

To better understand the role of tau in brain disease, Cohen Veterans Bioscience in partnership with In Silico Biosciences formed the MAPTA Alliance to drive efforts in developing predictive models of brain disease. This will be achieved by building mechanistic models based on Quantitative Systems Pharmacology (QSP) approaches and by integrating Causal Knowledge Base models such as the TBI Knowledge Map^TM. Immediate goals of the one-day workshop included:

• Launching MAPTA as an alliance to build an actionable computer model of tau pathology
• Introducing QSP modeling as a platform for modeling tau/disease biology
• Mapping the scientific knowledge base ready for modeling
• Prioritizing the Year 1 program activities for MAPTA

Dr. Magali Haas of Cohen Veterans Bioscience highlighted the proposed 3-year scientific roadmap for MAPTA, which includes exploring the intracellular function of tau (Year 1), understanding the trans-synaptic spreading of tau pathology through the brain (Year 2), and using tau’s known synaptic function to study neuronal network models relevant to TBI (Year 3).

During this process, MAPTA aims to recruit additional Alliance partners and align modeling efforts with areas of interest to industry. As described by Dr. Hugo Geerts of In Silico Biosciences, MAPTA is spearheading actionable deliverables, including a temporal model of intra-neuronal tau pathology in combination with a spatial-temporal model of human tauopathy progression with the end goal of bridging the gap between fundamental science and clinically relevant research.

As evidenced by discussion at the MAPTA Workshop, we are currently seeing only the tip of the iceberg with respect to tau pathology. In opening his talk on tau neurobiology, Dr. Kenneth Kosik, a professor in neuroscience at the University of California at Santa Barbara, expressed hope about tau as a possible druggable target: We’ve been in Death Valley for some time in this field, but I feel optimistic as we start thinking about tau in novel ways.” However, the difficulty resides in developing an in-depth understanding of the pathophysiological mechanisms of

key tauopathies prior to modeling attempts. Indeed, the development of effective computational tools with the goal to optimize the selection of putative targets require the gathering and evaluation of the existing knowledge space and the identification of key knowledge gaps. The alliance will work together to pursue this goal.

Members of MAPTA’s Scientific Advisory Board discussed areas of opportunities for modeling neuropathology. Some highlights include:

• Dr. Kosik outlined some of his work in human induced pluripotent stem cells using both advanced genetic techniques and state-of-the-art high-density electrophysiology measurements.
• Dr. Yasser Iturria-Medina from Alan Evan’s lab at the Montreal Neurological Institute presented a new analytical approach based on various human imaging modalities in large patient populations that will be used to identify both drivers of clinical tau pathology progression and clinical outcomes.
• Dr. Nigel J. Cairns of Washington University discussed the neuropathological differences of several tauopathies and how different tau isoforms are involved in diverse neurodegenerative diseases. He also addressed the current therapeutic strategies to use tau vaccinations.
• Dr. Kurt Brunden, University of Pennsylvania, has developed a method for enriching human brain-derived tau protein, which can be injected into wild-type mice to model how tau spreads and affects brain function.
• The AETIONOMY project, explained Dr. Martin Hofmann-Apitius of Fraunhofer-SCAI, uses a powerful analytical methodology organizing publicly available knowledge about neurodegenerative diseases to create mechanism-based disease taxonomies with the purpose of developing Knowledge Based Networks
• Dr. Roxana Carare, University of Southampton, presented her work on brain drainage and clearance of misfolded proteins; mechanisms that are thought to be impaired in many neurodegenerative disorders.
• Dr. Mony de Leon, NYU School of Medicine, highlighted the role of PET and fluid biomarkers in the clinical diagnosis of the tauopathies. He also presented a new PET based technique for measuring the clearance of CSF from the human brain and demonstrated predictive relationships between impaired CSF clearance and amyloid pathology. The PET clearance technique has the potential of providing quantitative data for modeling misfolded protein accumulations and clearance.
• In closing, Dr. Peter Davies, Northwell School of Medicine, described how utilizing tau antibodies may enable researchers to study a new pool” of tau extracellular tau that likely contributes to tau toxicity even in the absence of NFT neuropathology. He also discussed the role of neuroinflammation and the impact of tau pathology on neuropsychiatric symptoms.

To build on momentum from this workshop, working group meetings are planned for the second half of 2017. Through these on-going discussions, the MAPTA Alliance will start integrating preclinical and clinical data on tau biology into computational modeling efforts, prioritizing model development based on (1) the strength of the scientific literature, (2) appropriateness for modelling, and (3) relevancy from a drug discovery and development perspective. The objective is to develop a comprehensive and actionable modeling platform for identifying and validating druggable targets for tauopathies.

If you are interested in more details or would like to join the MAPTA Alliance, please contact [email protected].