Descrizione del progetto
Terapia cellulare sostitutiva per il morbo di Parkinson
Il morbo di Parkinson (PD, Parkinson’s Disease) è un disturbo neurodegenerativo progressivo caratterizzato dalla perdita di neuroni dopaminergici del mesencefalo. Poiché i trattamenti esistenti per il PD sono solo palliativi, ha suscitato grande interesse la terapia di sostituzione che utilizza neuroni dopaminergici del mesencefalo prodotti dalle cellule staminali pluripotenti umane. Lo scopo del progetto PreciseCellPD, finanziato dall’UE, è migliorare il processo di differenziazione in vitro delle cellule staminali pluripotenti umane così da produrre maggiori quantità di neuroni della sostanza nera, che sono le cellule necessarie per il trapianto. A tal fine, gli scienziati del progetto studieranno i fattori e i regolatori della trascrizione che controllano in vitro le specifiche dei neuroni della sostanza nera prodotti dalle cellule staminali pluripotenti umane.
Obiettivo
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
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
17177 Stockholm
Svezia