POST DOCTORAL RESEARCHER The Florey Institure of Neuroscience and Mental Health Melbourne, Victoria, Australia
Abstract: Parkinson’s disease continues to be at the centre of hPSC replacement therapy with several clinical trials using human pluripotent suicide cell (PSC)-derived dopamine progenitors currently underway. While promising, there remains an ongoing need for technology/therapeutic refinement. There persists a need to address the purity of these transplants and the potential for tissue overgrowth risk, regardless of how small. One strategy to perturb concerns of cellular overgrowth is through genomic integration of a suicide-gene systems into the PSC donor material to enable ablation of proliferative cells or the graft entirely post-transplantation. In an advancement, here we developed a PSC line containing a novel suicide cell-based system that can be regulated by tissue-specific promoters to activate the suicide gene switch within both cell and non-cell autonomous identities at specific developmental trajectories of the grafted neural progenitors through administration of a chemical pro-drug.
We validate selective ablation of immature cell lineage and non-neuronal populations in vitro when the new line was differentiated toward dopamine neurons, resulting in a significant 3-fold enrichment of MAP2+ neurons and total DA neurons (2.6-fold).
We similarly demonstrate the ability to selectively ablate non-neuronal and proliferative populations at 10 weeks following transplantation of midbrain-derived progenitors into immunecompromised PD rodents, with functional recovery restored by 12 weeks. Histological assessment of grafts at 18 weeks revealed a significant reduction in the presence of proliferative cells, glia and non-neural cells complimented by a 35% increase in neurons and DA neurons. This new stem cell tool holds significant implications for improving the safety, purity and predictability of hPSC-derived neural transplants to treat diseases such as PD.
