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

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. Overall design: Gene expression profile of human xenografts transplanted into host mouse brains. Mixes species RNAseq with 3 biological replicates of 2 xenograft types (midbrain dopamine neurons differentated from embryonic stem cells transplanted into an Untreated or GDNF treated host).