Speaker
Description
Parkinson’s disease (PD) is a pervasive neurodegenerative disorder characterized by a loss of dopaminergic neurons starting from the substantia nigra, which triggers motor and cognitive symptoms. Existing treatments such as dopamine replacement therapies and deep brain stimulation (DBS) provide symptomatic relief, but they are limited by side effects and transient efficacy. Cell replacement therapies (CRTs) are emerging as a promising alternative in ongoing clinical trials, where mesencephalic dopaminergic neurons (mesDAs) derived from human pluripotent stem cells are transplanted into the striatum to restore dopamine functionality.
Cell survival, healthy neural maturation and functional integration of mesDAs into host brain circuits represent major challenges in CRTs. Behavioral improvements can require months in animal studies, and up to two years in humans, underscoring the clinical need for enhancing cell maturation and functionality. Temporal interference (TI) stimulation is a revolutionary technique for non-invasive DBS in the clinic (Grossman et al., 2017), which has shown potential to increase neural differentiation and functionality in vitro and in vivo (Peressotti et al., in progress). However, the optimal TI stimulation parameters for improving CRT outcomes remain unknown, due to the wide range of potential protocols.
Understanding the functionality and maturation dynamics of transplanted cells is a complex endeavor requiring diverse and longitudinal readouts, which are challenging to obtain in vivo. Thus, a high-throughput in vitro platform will be developed to systematically evaluate the influence of TI on an in vitro CRT model. The construct will consist in 3D spheroids from primary striatal cells, mixed with optogenetically-tagged mesDA progenitors. The impact of different stimulation protocols on differentiation, maturation, and functionality will be evaluated using longitudinal optogenetics-based electrophysiological studies, dopamine release quantifications, immunofluorescence and mRNA sequencing at multiple time points. The results will be validated in vivo, towards a highly translatable approach to improve the efficacy of CRTs for PD.
| Author(s) | Sofia Peressotti, Valerio Zerbi |
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| Affiliation(s) | University of Geneva, Psychiatry Department, Campus Biotech (1202, Geneva) |
