Modelling of a targeted nanotherapeutic 'stroma' to deliver the cytokine LIF, or XAV939, a potent inhibitor of Wnt-ß-catenin signalling, for use in human fetal dopaminergic grafts in Parkinson's disease.

The endogenous reparative capacity of the adult human brain is low, and chronic neurodegenerative disorders of the central nervous system represent one of the greatest areas of unmet clinical need in the developing world. Novel therapeutic strategies to treat them include: (i) growth factor delivery to boost endogenous repair and (ii) replacement cell therapy, including replacing dopaminergic neurons to treat Parkinson's disease (PD). However, these approaches are restricted not only by rapid degradation of growth factors, but also by the limited availability of cells for transplant and the poor survival of implanted cells that lack the necessary stromal support. We therefore hypothesised that provision of a transient artificial stroma for paracrine delivery of pro-survival factors could overcome both of these issues. Using leukaemia inhibitory factor (LIF) - a proneural, reparative cytokine - formulated as target-specific poly(lactic-co-glycolic acid) (PLGA) nano-particles (LIF-nano-stroma), we discovered that attachment of LIF-nano-stroma to freshly isolated fetal dopaminergic cells improved their survival fourfold: furthermore, in vivo, the number of surviving human fetal dopaminergic cells tended to be higher at 3 months after grafting into the striatum of nude rats, compared with controls treated with empty nanoparticles. In addition, we also analysed the effect of a novel nano-stroma incorporating XAV939 (XAV), a potent inhibitor of the developmentally important Wnt-ß-catenin signalling pathway, to investigate whether it could also promote the survival and differentiation of human fetal dopaminergic precursors; we found that the numbers of both tyrosine-hydroxylase-positive neurons (a marker of dopaminergic neurons) and total neurons were increased. This is the first demonstration that LIF-nano-stroma and XAV-nano-stroma each have pro-survival effects on human dopaminergic neurons, with potential value for target-specific modulation of neurogenic fate in cell-based therapies for PD.

Cell-based therapies for Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, classically characterized by a triad of motor features: bradykinesia, rigidity and resting tremor. Neurodegeneration in PD critically involves the dopaminergic neurons of the substantia nigra pars compacta, which results in a severe reduction in dopamine levels in the dorsal striatum. However, the disease also exhibits extensive non-nigral pathology and as many non-motor as motor features. Nevertheless, owing to the relatively circumscribed nature of the nigrostriatal lesion in PD, dopaminergic cell transplantation has emerged as a potentially reparative therapy for the disease. Sources for such cells are varied and include the developing ventral mesencephalon, several autologous somatic cell types, embryonic stem cells and induced pluripotent stem cells. In this article, we review the origins of dopaminergic transplantation for PD and the emergent hunt for a suitable long-term source of transplantable dopaminergic neurons.