Thymidylate synthase disruption to limit cell proliferation in cell therapies DOI Creative Commons
Rocío Maldonado, Hossam Montaser, Inkeri Soppa

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 26, 2023

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 novel metabolic safety system to control proliferation without added genetic elements. We inactivated key enzyme nucleotide metabolism, TYMS , in several lines, thus obtaining that proliferate only when supplemented with exogenous thymidine but fail replicate its absence. Under supplementation, -/- pluripotent stem normally, produce teratomas differentiate into potentially therapeutic types such as pancreatic beta cells. After differentiation, the postmitotic do not require function, seen by prolonged vivo production human insulin implanted mice. Hence, this method allows robust culture manufacture while mitigating uncontrolled growth transplanted One Sentence Summary: Genetic disruption DNA synthesis prevents therapies affecting function.

Language: Английский

Thymidylate synthase disruption to limit cell proliferation in cell therapies DOI Creative Commons
Rocío Maldonado, Hossam Montaser, Inkeri Soppa

et al.

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(8), P. 2535 - 2548

Published: June 12, 2024

Stem and progenitor cells hold great promise for regenerative medicine gene therapy approaches. However, transplantations of living entail a fundamental risk unwanted growth, potentially exacerbated by CRISPR-Cas9 or other genetic manipulations. Here, we describe safety system to control cell proliferation while allowing robust efficient manufacture, without any added elements. Inactivating TYMS, key nucleotide metabolism enzyme, in several lines resulted that proliferate only when supplemented with exogenous thymidine. Under supplementation, TYMS-/--pluripotent stem proliferate, produce teratomas successfully differentiate into therapeutic types such as pancreatic beta-cells. Our results suggest supplementation thymidine affects proliferation, but not the function cell-derived cells. After differentiation, postmitotic do require vitro vivo, shown production functional human insulin mice up 5 months after implantation stem-cell derived tissue.

Language: Английский

Citations

0
Stroke-related gene expression profiles across species: A meta-analysis DOI Creative Commons
Ruslan Rust

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 14, 2023

Abstract Stroke patients are often left with permanent disabilities no regenerative treatment options. Unbiased RNA sequencing studies decoding the transcriptional signature of stroked tissue hold promise to identify new potential targets and pathways directed improve for stroke patients. Here, gene expression profiles across different time points, species, models were compared using NCBI GEO database. In total, 32 datasets from mice, rats, humans, primates included, exploring differences in healthy brain tissue. Distinct changes pathway enrichment revealed heterogenicity pathology stroke-related e.g., inflammatory responses, vascular repair, remodelling cell proliferation adhesion but also diverse general, stroke-unrelated that have be carefully considered when evaluating promising therapeutic targets.

Language: Английский

Citations

0
Thymidylate synthase disruption to limit cell proliferation in cell therapies DOI Creative Commons
Rocío Maldonado, Hossam Montaser, Inkeri Soppa

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 26, 2023

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 novel metabolic safety system to control proliferation without added genetic elements. We inactivated key enzyme nucleotide metabolism, TYMS , in several lines, thus obtaining that proliferate only when supplemented with exogenous thymidine but fail replicate its absence. Under supplementation, -/- pluripotent stem normally, produce teratomas differentiate into potentially therapeutic types such as pancreatic beta cells. After differentiation, the postmitotic do not require function, seen by prolonged vivo production human insulin implanted mice. Hence, this method allows robust culture manufacture while mitigating uncontrolled growth transplanted One Sentence Summary: Genetic disruption DNA synthesis prevents therapies affecting function.

Language: Английский

Citations

0