ND Biosciences

ND Biosciences’ Integrated Drug Discovery Platforms Allow Dissecting the Mode of Action of Candidate Therapeutics

ND Biosciences’ drug discovery platforms include an integrated suite of models that reproduce not only the key pathological signatures, but also relevant processes underlying protein aggregation in human brain pathology. 

These models include: i) cell-free systems allowing real-time assessment of protein aggregation kinetics in vitro, ii) complex cellular and neuronal models that reproduce different stages and key processes underlying protein aggregation, toxicity and Lewy body formation in neurons, and (iii) different animal models of protein aggregation and related neurotoxicity and behavioral deficits. These integrated platforms enable comprehensive assessment of the anti-aggregation properties of potential therapeutic molecules, as well as determining their mode of action.

As ND Biosciences’ co-founders recently discuss in an elaborate review published in Nature Reviews Neurosciences, the great majority of neuronal models currently used in Parkinson’s disease (PD) research do not reproduce the structural features or key processes underlying protein aggregation in human brains. This could be a key factor as to why most therapeutic candidates that show promising results in existing models fail in the clinic. Based on 10 years of R&D at the EPFL, ND Biosciences drug discovery platforms comprise a unique portfolio of neuronal models that reproduce distinct stages of protein pathology, and allow interrogation of therapeutic effects at early and late stages of diseases. These models were characterized at unprecedented detail using a combination of biochemical, imaging, and proteomic techniques, and include neuronal models that mimic: i)  early stages of de novo inclusion formation in Parkinson’s disease on the basis of expressing α-Syn in a specific strain of mice (Fares et al., 2016), ii) extracellular protein aggregation and mediated toxicity upon treatment with specific mixtures of pathologic α-Syn preparations (Mahul-Mellier et al., 2015), iii) intermediate stages of α-Syn protein uptake and seeding of endogenous α-Syn aggregation following treatment with preformed α-Syn fibrils (Mahul-Mellier et al., 2019), and iv) late stages of α-Syn aggregation into Lewy body (LB) inclusions that is concomitant with neurotoxic effects, phenomena that were previously unattainable in any of the previous models utilized for drug discovery (Mahul-Mellier et al., 2020). Utilizing these models, ND Biosciences is now able to reproduce different pathological stages and processes in living neurons, and to develop small molecules and biologics that specifically target these aberrant mechanisms.