Discovery and validation of human genomic safe harbor sites for gene and cell therapies.

Autor:	Aznauryan E; Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.; Systems Biology Program, Life Science Zürich Graduate School, Zürich, Switzerland.; Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Yermanos A; Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.; Institute of Microbiology, ETH Zürich, Zürich, Switzerland.; Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland., Kinzina E; McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Devaux A; Department of Biomedicine, University of Basel, Basel, Switzerland., Kapetanovic E; Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland., Milanova D; Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Church GM; Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Reddy ST; Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
Jazyk:	angličtina
Zdroj:	Cell reports methods [Cell Rep Methods] 2022 Jan 14; Vol. 2 (1), pp. 100154. Date of Electronic Publication: 2022 Jan 14 (Print Publication: 2022).
DOI:	10.1016/j.crmeth.2021.100154
Abstrakt:	Existing approaches to therapeutic gene transfer are marred by the transient nature of gene expression following non-integrative gene delivery and by safety concerns due to the random mechanism of viral-mediated genomic insertions. The disadvantages of these methods encourage future research in identifying human genomic sites that allow for durable and safe expression of genes of interest. We conducted a bioinformatic search followed by the experimental characterization of human genomic sites, identifying two that demonstrated the stable expression of integrated reporter and therapeutic genes without malignant changes to the cellular transcriptome. The cell-type agnostic criteria used in our bioinformatic search suggest widescale applicability of identified sites for engineering of a diverse range of tissues for clinical and research purposes, including modified T cells for cancer therapy and engineered skin to ameliorate inherited diseases and aging. In addition, the stable and robust levels of gene expression from identified sites allow for the industry-scale biomanufacturing of proteins in human cells. Competing Interests: ETH Zürich and Harvard University have filed for patent protection on the technology described herein, and E.A., D.M., S.T.R., and G.M.C are named as co-inventors on the patent. The full disclosure for G.M.C. is available at http://arep.med.harvard.edu/gmc/tech.html. (© 2021 The Author(s).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu