en
Doctoral thesis
English

Safety switch system to secure neural cell therapies

ContributorsLocatelli, Manon
Number of pages168
Imprimatur date2021-12-14
Defense date2021-12-14
Abstract

The increase in human lifespan is associated with the predominance of age-related diseases, and particularly neurodegenerative disorders, such as Parkinson’s disease. The latter is mainly characterized by the loss of dopaminergic neurons1, which secrete dopamine. New cell therapy approaches hold an unprecedented potential of curative treatment through the transplantation of therapeutic cells. The clinical results of the transplantation of fetal neurons in Parkinson’s patients have shown promising results2, however this non-sustainable source of dopaminergic neurons raises logistical and ethical problems. Pluripotent stem cells (PSC) have risen great hopes in tissue regeneration and repair based on their capacity of unlimited self-renewal and their ability to differentiate into virtually all cell types3. Furthermore, PSC can be derived from embryonic tissue (embryonic stem cells, ePSC) or through reprogramming of adult cells (induced pluripotent stem cells, iPSC). However, the unique PSC feature of unlimited cell division may lead to tumor formation and represents a major limitation for their clinical use. Indeed, even using optimal differentiation protocols, some poorly differentiated proliferating cells may persist in the PSC-derived transplant. The most promising approach to overcome this issue is the addition of a safety switch, i.e. transgenic insertion of a suicide gene that can be activated by a suicide inducer, thereby allowing the elimination of transplanted cells in case of tumor formation. Most safety switch technologies eliminate the entire transplant. However, in my studies, I have focused on a safety switch that eliminates proliferating cells, while preserving post-mitotic neurons. This approach based on the thymidine kinase from the Herpes simplex virus (HSV-TK) driven by a cell cycle-dependent promoter (Ki67) was developed in our laboratory. The proof of concept has been done previously4, however in its early form, it suffered from at least two drawbacks: i) the dose of the relatively toxic suicide inducing nucleoside Ganciclovir (GCV) required to eliminate proliferating cells was too high for clinical use and ii) while the system allow to prevent formation of PSC-derived tumors, it was not able to eliminate tumors once they were established. The aim of my thesis project was i) an improved understanding of the biology and the pharmacology underlying the HSV-TK /nucleoside-based safety switch, and ii) to design, based on these results, an improved safety switch.

eng
Keywords
  • Suicide gene
  • Penciclovir
  • Ganciclovir
  • Stem cells
  • Cell therapy
Citation (ISO format)
LOCATELLI, Manon. Safety switch system to secure neural cell therapies. 2021. doi: 10.13097/archive-ouverte/unige:159940
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Creation03/14/2022 8:47:00 AM
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