Abstract
Cell therapies based on pluripotent stem cells (PSC), have opened new therapeutic strategies for neurodegenerative diseases. However, insufficiently differentiated PSC can lead to tumor formation. Ideally, safety switch therapies should selectively kill proliferative transplant cells while preserving post-mitotic neurons. In this study, we evaluated the potential of nucleoside analogs and thymidine kinase-based suicide genes. Among tested thymidine kinase variants, the humanized SR39 (SR39h) variant rendered cells most sensitive to suicide induction. Unexpectedly, post-mitotic neurons with ubiquitous SR39h expression were killed by ganciclovir, but were spared when SR39h was expressed under the control of the cell cycle-dependent Ki67 promoter. The efficacy of six different nucleoside analogs to induce cell death was then evaluated. Penciclovir (PCV) showed the most interesting properties with an efficiency comparable to ganciclovir (GCV), but low toxicity. We tested three nucleoside analogs in vivo: at concentrations of 40 mg/kg/day, PCV and GCV prevented tumor formation, while acyclovir (ACV) did not. In summary, SR39h under the control of a cell cycle-dependent promoter appears most efficient and selective as safety switch for neural transplants. In this setting, PCV and GCV are efficient inducers of cell death. Because of its low toxicity, PCV might become a preferred alternative to GCV.
Highlights
The increase in human lifespan is associated with the predominance of age-related diseases, in particular neurodegenerative disorders, such as Parkinson’s disease
Pluripotent stem cells (PSC) have great potential in tissue regeneration and repair based on their capacity for unlimited self-renewal and their ability to differentiate into virtually all cell types [3]
Pluripotent stem cells (PSC) hold great promise for future regenerative therapies, in particular in the context of neurodegenerative diseases. Their proliferative potential is a potential hazard, as the risk of tumor formation must be controlled before a transfer into clinics
Summary
The increase in human lifespan is associated with the predominance of age-related diseases, in particular neurodegenerative disorders, such as Parkinson’s disease The latter is characterized by the loss of dopaminergic neurons [1]. Pluripotent stem cells (PSC) have great potential in tissue regeneration and repair based on their capacity for unlimited self-renewal and their ability to differentiate into virtually all cell types [3]. This unique feature of unlimited cell division may lead to tumor formation and represents the major limitation for their clinical use
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