論文 - 詳細
| RRC ID | 77293 |
|---|---|
| 著者 | Pavani G, Laurent M, Fabiano A, Cantelli E, Sakkal A, Corre G, Lenting PJ, Concordet JP, Toueille M, Miccio A, Amendola M. |
| タイトル | Ex vivo editing of human hematopoietic stem cells for erythroid expression of therapeutic proteins. |
| ジャーナル | Nat Commun |
| Abstract |
Targeted genome editing has a great therapeutic potential to treat disorders that require protein replacement therapy. To develop a platform independent of specific patient mutations, therapeutic transgenes can be inserted in a safe and highly transcribed locus to maximize protein expression. Here, we describe an ex vivo editing approach to achieve efficient gene targeting in human hematopoietic stem/progenitor cells (HSPCs) and robust expression of clinically relevant proteins by the erythroid lineage. Using CRISPR-Cas9, we integrate different transgenes under the transcriptional control of the endogenous α-globin promoter, recapitulating its high and erythroid-specific expression. Erythroblasts derived from targeted HSPCs secrete different therapeutic proteins, which retain enzymatic activity and cross-correct patients' cells. Moreover, modified HSPCs maintain long-term repopulation and multilineage differentiation potential in transplanted mice. Overall, we establish a safe and versatile CRISPR-Cas9-based HSPC platform for different therapeutic applications, including hemophilia and inherited metabolic disorders. |
| 巻・号 | 11(1) |
| ページ | 3778 |
| 公開日 | 2020-7-29 |
| DOI | 10.1038/s41467-020-17552-3 |
| PII | 10.1038/s41467-020-17552-3 |
| PMID | 32728076 |
| PMC | PMC7391635 |
| MeSH | Animals CRISPR-Cas Systems / genetics Cell Engineering / methods* Cell Line Female Gene Editing* Gene Expression Regulation Hematopoietic Stem Cell Transplantation / methods* Hematopoietic Stem Cells / metabolism* Hemophilia A / therapy Humans Metabolic Diseases / therapy Mice Promoter Regions, Genetic / genetics Transplantation, Autologous / methods Transplantation, Heterologous alpha-Globins / genetics alpha-Globins / metabolism |
| IF | 12.121 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 31 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HUDEP-2(RCB4557) |