The development of cell therapeutics may be delayed by the mismatch between mouse models of disease and their actual human counterparts. Mouse models that faithfully replicate CNS disease genetics, natural history and pathology are scarce, and limited to selected monogenic hereditary disorders. More typically, mouse models are established and selected on the basis of their ability to replicate discrete aspects of disease histopathology, often without regard to pathogenesis or normal time course of disease progression. For instance, chemotoxic models of Parkinson’s disease, including both 6-hydroxydopamine and MPTP exposure, have evolved because of their selective depletion of nigral dopaminergic neurons and associated neurological dysfunction, yet neither reproduces the human-specific circuitry or disease environment of Parkinson’s patients, who may handle dopaminergic grafts very differently from their murine avatars. This distinction was made clear by the inability of experiments using these mouse models to predict the dyskinesias that plagued fetal tissue transplants into Parkinson’s patients, an unforeseen sequela that slowed progress in that field for over a decade (Barker et al., 2015).
