Reference - Detail
| RRC ID | 59765 |
|---|---|
| Author | Wang H, Liu Z, Li C, Gil S, Papayannopoulou T, Doering CB, Lieber A. |
| Title | High-level protein production in erythroid cells derived from in vivo transduced hematopoietic stem cells. |
| Journal | Blood Adv |
| Abstract |
We developed an in vivo hematopoietic stem cell (HSC) transduction approach that involves HSC mobilization from the bone marrow into the peripheral bloodstream and the IV injection of an integrating, helper-dependent adenovirus (HDAd5/35++) vector system. HDAd5/35++ vectors target human CD46, a receptor that is abundantly expressed on primitive HSCs. Transgene integration is achieved by a hyperactive Sleeping Beauty transposase (SB100x) and transgene marking in peripheral blood cells can be increased by in vivo selection. Here we directed transgene expression to HSC-derived erythroid cells using β-globin regulatory elements. We hypothesized that the abundance and systemic distribution of erythroid cells can be harnessed for high-level production of therapeutic proteins. We first demonstrated that our approach allowed for sustained, erythroid-lineage specific GFP expression and accumulation of GFP protein in erythrocytes. Furthermore, after in vivo HSC transduction/selection in hCD46-transgenic mice, we demonstrated stable supraphysiological plasma concentrations of a bioengineered human factor VIII, termed ET3. High-level ET3 production in erythroid cells did not affect erythropoiesis. A phenotypic correction of bleeding was observed after in vivo HSC transduction of hCD46+/+/F8-/- hemophilia A mice despite high plasma anti-ET3 antibody titers. This suggests that ET3 levels were high enough to provide sufficient noninhibited ET3 systemically and/or locally (in blood clots) to control bleeding. In addition to its relevance for hemophilia A gene therapy, our approach has implications for the therapy of other inherited or acquired diseases that require high levels of therapeutic proteins in the blood circulation. |
| Volume | 3(19) |
| Pages | 2883-2894 |
| Published | 2019-10-8 |
| DOI | 10.1182/bloodadvances.2019000706 |
| PII | bloodadvances.2019000706 |
| PMID | 31585952 |
| PMC | PMC6784527 |
| MeSH | Animals Erythroid Cells / metabolism* Hematopoietic Stem Cells / metabolism* Humans Mice |
| IF | 4.91 |
| Times Cited | 4 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 9 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | HUDEP-2(RCB4557) |