Thymidylate synthase disruption to limit cell proliferation in cell therapies

Rocio Maldonado Sartori, Hossam Montaser, Inkeri Sigrid Esteri Soppa, Solja Eurola, Juhana Heikki Juutila, Melanie Balaz, Henri Puttonen, Timo Otonkoski, Jonna Saarimäki-Vire, Kirmo Wartiovaara

Research output: Contribution to journalArticleScientific

Abstract

Engineered cells hold great promise for regenerative medicine and gene therapy. However, living cell products entail a fundamental biological risk of unwanted growth. Here, we describe a novel metabolic safety system to control cell proliferation without added genetic elements. We inactivated a key enzyme for nucleotide metabolism, TYMS, in several cell lines, thus obtaining cells that proliferate only when supplemented with exogenous thymidine but fail to replicate in its absence. Under supplementation, TYMS-/- pluripotent stem cells proliferate normally, produce teratomas and differentiate into potentially therapeutic cell types such as pancreatic beta cells. After differentiation, the postmitotic cells do not require thymidine to function, as seen by prolonged in vivo production of human insulin in implanted mice. Hence, this method allows robust cell culture and manufacture while mitigating the risk of uncontrolled growth of transplanted cells.
Original languageEnglish
JournalMolecular therapy
ISSN1525-0016
DOIs
Publication statusIn preparation - 12 Jun 2024
MoE publication typeB1 Journal article

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