Targeted Genome Editing in Human Repopulating Hematopoietic Stem Cells
| العنوان: | Targeted Genome Editing in Human Repopulating Hematopoietic Stem Cells |
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| المؤلفون: | Mirjam van der Burg, Giulia Schiroli, Bernhard Gentner, Angelo Lombardo, Giulia Escobar, Luigi Naldini, Michael C. Holmes, Roberta Mazzieri, Davide Moi, Chiara Bonini, Pietro Genovese, Philip D. Gregory, Claudia Firrito, Eugenio Montini, Andrea Calabria, Tiziano Di Tomaso |
| المساهمون: | Immunology, Genovese, P, Schiroli, G, Escobar, G, Di Tomaso, T, Firrito, C, Calabria, A, Moi, D, Mazzieri, R, Bonini, MARIA CHIARA, Holmes, Mc, Gregory, Pd, van der Burg, M, Gentner, B, Montini, E, Lombardo, ANGELO LEONE, Naldini, Luigi |
| المصدر: | Nature Nature, 510(7504), 235-+. Nature Publishing Group |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Male, DNA, Complementary, Genetic enhancement, Transgene, Antigens, CD34, Biology, Gene delivery, X-Linked Combined Immunodeficiency Diseases, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genome editing, Animals, Humans, 030304 developmental biology, Genetics, 0303 health sciences, Transcription activator-like effector nuclease, Multidisciplinary, Genome, Human, Hematopoietic Stem Cell Transplantation, Gene targeting, Endonucleases, Fetal Blood, Hematopoietic Stem Cells, Hematopoiesis, Cell biology, Haematopoiesis, 030220 oncology & carcinogenesis, Mutation, Gene Targeting, Stem cell, Interleukin Receptor Common gamma Subunit, Targeted Gene Repair |
| الوصف: | Targeted genome editing by artificial nucleases has brought the goal of site-specific transgene integration and gene correction within the reach of gene therapy. However, its application to long-term repopulating haematopoietic stem cells (HSCs) has remained elusive. Here we show that poor permissiveness to gene transfer and limited proficiency of the homology-directed DNA repair pathway constrain gene targeting in human HSCs. By tailoring delivery platforms and culture conditions we overcame these barriers and provide stringent evidence of targeted integration in human HSCs by long-term multilineage repopulation of transplanted mice. We demonstrate the therapeutic potential of our strategy by targeting a corrective complementary DNA into the IL2RG gene of HSCs from healthy donors and a subject with X-linked severe combined immunodeficiency (SCID-X1). Gene-edited HSCs sustained normal haematopoiesis and gave rise to functional lymphoid cells that possess a selective growth advantage over those carrying disruptive IL2RG mutations. These results open up new avenues for treating SCID-X1 and other diseases. |
| اللغة: | English |
| تدمد: | 1476-4687 0028-0836 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2bd42ad468e0dd0a71e6f47c28b390f6 http://europepmc.org/articles/PMC4082311 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2bd42ad468e0dd0a71e6f47c28b390f6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14764687 00280836 |
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