Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson’s Disease

Abstract

The derivation of neurotransmitter and region-specific neuronal populations from human pluripotent stem cells (PSC) provides impetus for advancing cell therapies into the clinic. At the forefront is our ability to generate ventral midbrain (VM) dopaminergic (DA) progenitors, suitable for transplantation in Parkinson's disease (PD). Pre-clinical studies, however, have highlighted the low proportion of DA neurons within these grafts and their inferior plasticity by comparison to human fetal donor transplants.Here we sought to examine whether modification of the host environment, through viral delivery of a developmentally critical molecule, glial cell line-derived neurotrophic factor (GDNF), could improve graft survival, integration and function in Parkinsonian rodents. Utilising LMX1A-and PITX3-GFP hPSC reporter lines, we tracked the response of DA progenitors implanted into either a GDNF-rich environment, or in a second group, after a 3-week delay in onset of exposure. We found that early exposure of the graft to GDNF promoted survival of DA and non-DA cells, leading to enhanced motor recovery in PD rats. Delayed overexpression of intrastriatal GDNF also promoted motor recovery in transplanted rats, through alternate selective mechanisms including enhanced A9/A10 specification, increased DA graft plasticity, greater activation of striatal neurons and elevated DA metabolism. Lastly, transcriptional profiling of the grafts highlighted novel genes underpinning these changes. Collectively these results demonstrate the potential of targeted neurotrophic gene therapy strategies to improve human PSC graft outcomes.

Human Pluripotent Stem Cells-Based Therapies for Neurodegenerative Diseases: Current Status and Challenges

“…However, the overall proportion of hESC-derived DANs within the grafted region remains low, due in part to their poor survival immediately following transplantation. Glial cell line-derived neurotrophic factor (GDNF) has recently been shown to increase the survival, plasticity, and functional integration of hPSC-derived VM DA progenitor grafts, in a time post-transplantation-dependent manner [18]. Interestingly, a new cell type resembling perivascular-like cells, called vascular leptomeningeal cells (VLMC), has very recently been identified in hESC-DANergic grafts [52].…”

Neurotrophic Factors in Parkinson’s Disease: Clinical Trials, Open Challenges and Nanoparticle-Mediated Delivery to the Brain

“…A key requirement for cell-replacement therapy to be successful is that engrafted neurons stay alive and integrate into resident neuronal networks by forming new synaptic contacts ( Parmar et al, 2020 ). NTFs delivered systemically with NPs could serve as a supporting tool in these therapies, keeping neurons alive and facilitating the establishment of neuronal contacts ( Gantner et al, 2020 ).…”

Embryonic stem cells go from bench to bedside for Parkinson’s disease

“…In particular, strategies to improve graft purity and limit the expansion of off-target/non-dopaminergic populations through the pre-selection of correctly specified progenitors prior to grafting 7 or elimination of un-wanted populations through suicidebased approaches after implantation (C.L.P., unpublished data). Added to this is the consideration that additional trophic cues may enhance graft survival, fate acquisition, and plasticity as recently demonstrated, 8 or whether homotopic transplants, into the site of cell loss, is feasible in the human brain. Finally, while the consensus surrounding current and proposed trials is that a period of immunosuppression is needed after grafting, whether engineered universal donor cells can circumvent this for neural grafting remains to be seen.…”