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Viral Delivery Of GDNF Promotes Functional Integration Of Human Stem Cell Grafts In Parkinson’s Disease

ABSTRACT: Dopaminergic neurons (DAn), generated from human pluripotent stem cells (hPSC), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson’s disease (PD). However, pre-clinical studies have highlighted the low proportion of DAn within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAn implanted into either a GDNF-rich environment, or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAn, leading to enhanced motor recovery in PD rats. Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity and dopamine metabolism. Transcriptional profiling revealed a role for MAPK-signalling downstream of GDNF. Collectively these results demonstrate the potential of neurotrophic gene therapy strategies to improve hPSC graft outcomes.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE143136 | GEO | 2020/01/06

REPOSITORIES: GEO

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