A Drug Discovery Platform to Prioritize Development of Natural Product Neuromodulators for Treating Cognitive Impairment

PROJECT SUMMARY Mild Cognitive Impairment (MCI) is one of the earliest and most noticeable symptoms associated with Alzheimer’s Disease (AD) and other AD Related Dementias (ADRD). There is no cure for ADRD, and conventional treatments only target more disease stages. Notably, MCI associated with AD typically occurs after AD biomarkers (related to β-amyloid and tau pathologies) are detectable in patients, creating a narrow window prior to MCI-AD onset and diagnosis, termed preclinical AD, where interventions slowing MCI onset have the potential to greatly improve patient quality of life and dramatically reduce costs of AD care at large. However, developing pharmaceutical treatments for preclinical AD must meet high safety margins given the duration of treatment, and past attempts have failed to show efficacy. Recently, approvals of antidepressants like ketamine and brexanolone (both 2019) and the resurgence of psychedelic research has highlighted the power of neuroplasticity modifiers – compounds driving the creation or modulation of synaptic connections within the brain – for modifying neurological function to impact mental health. Engaging neuroplasticity mechanisms through pharmacological means or holistic approaches (i.e. exercise & dietary changes) has been shown to positively enhance cognition and memory. Notably, some of the most potent neuroplasticity modulators are Natural Products (NPs) derived from medicinal plants and herbs used by humans for centuries. As such, NPs have been the subject of numerous studies investigating their potential to improve cognition and progression to MCI in AD. However, incomplete descriptions of NP molecular targets, mechanisms of action, stability, purity, potency and bioavailability have largely prevented their development as clinical drug candidates. What’s more, the quantity of known NPs found in botanical products numbers in the tens of thousands. To identify and develop psychoactive natural products that impact neuroplasticity and can slow MCI onset, Sensorium Therapeutics is expanding the capacity of their Biodynamic Discovery PlatformTM (BDP). Our novel BDPTM leverages AI-assisted analysis of ethnobotanical data and medicinal chemistry coupled with in vitro high-throughput screening using human iPSCs to provide an effective drug development pipeline for identifying novel NPs as MCI-AD treatments. Our platform has already led to the identification of a leading natural product drug candidate for depression and anxiety. Additionally, we have identified a class of botanically-derived alkaloid compounds that have favorable CNS pharmacological profiles, excellent chemical and in vitro safety, and are linked to improving cognitive function in humans. The overarching goal of this Fast Track proposal is to expand our BDPTM to include scalable cellular/neuronal readouts of neuroplasticity while incorporating MCI-AD in vitro models (Phase I) and identify and validate NP candidate efficacy for MCI-AD treatment (Phase II). Successful completion of this Fast Track project will generate NP candidates for further development and demonstrate efficacy for Sensorium’s Biodynamic Discovery PlatformTM in identifying lead candidates for MCI-AD treatments.