A precision cell replacement strategy for  parkinson’s disease
Parkinson’s disease (PD) is a progressive incurable neurodegenerative disorder characterized by the loss of substantia nigra neurons (A9/SNs), a subset of midbrain dopaminergic neurons (mDAs) that are required for functional re-innervation of the striatum. Current treatments for PD are symptomatic and do not prevent disease progression. Proof-of-concept clinical studies using human fetal midbrain tissue for transplantation have shown that replacement of mDAs can change the course of PD. Human pluripotent stem cells (hPSCs) are currently used to generate mDAs for cell replacement therapy in clinical trials. However, our single-cell RNA-sequencing analysis of these preparations revealed that they comprise a complex mixture of cell types, including mDAs but also excessive vascular progenitor-like cells and serotonin neurons, thought to drive dyskinesias.
Selective generation of A9/SNs for PD cell replacement therapy remains thus a major challenge. Here I propose to identify how human adult A9/SNs are generated in order to develop a novel cell type-specific precision cell replacement therapy for PD. I hypothesize that a yet undefined network of transcription factors and regulators control A9/SN subtype specification, and that such factors can be used to engineer A9/SNs starting from hPSCs or astrocytes, moving the field beyond the state of the art.
This will be achieved by: 1) Using cutting-edge CRISPR and single cell methodologies to identify the factors controlling the specification of human A9/SNs; and 2) developing two novel cell replacement strategies for PD, involving either transplantation of hPSC-derived progenitors forward-programmed into A9/SNs or reprogramming of endogenous striatal glia in situ into A9/SNs, using a method we recently developed.
I expect PreciseCellPD will generate groundbreaking knowledge of the mechanisms controlling the generation of human A9/SNs and will set the basis of a novel and transformative precision cell replacement therapy for PD