| RRC ID |
77307
|
| 著者 |
Li C, Wang H, Georgakopoulou A, Gil S, Yannaki E, Lieber A.
|
| タイトル |
In Vivo HSC Gene Therapy Using a Bi-modular HDAd5/35++ Vector Cures Sickle Cell Disease in a Mouse Model.
|
| ジャーナル |
Mol Ther
|
| Abstract |
We have recently reported that, after in vivo hematopoietic stem cell/progenitor (HSPC) transduction with HDAd5/35++ vectors, SB100x transposase-mediated γ-globin gene addition achieved 10%-15% γ-globin of adult mouse globin, resulting in significant but incomplete phenotypic correction in a thalassemia intermedia mouse model. Furthermore, genome editing of a γ-globin repressor binding site within the γ-globin promoter by CRISPR-Cas9 results in efficient reactivation of endogenous γ-globin. Here, we aimed to combine these two mechanisms to obtain curative levels of γ-globin after in vivo HSPC transduction. We generated a HDAd5/35++ adenovirus vector (HDAd-combo) containing both modules and tested it in vitro and after in vivo HSPC transduction in healthy CD46/β-YAC mice and in a sickle cell disease mouse model (CD46/Townes). Compared to HDAd vectors containing either the γ-globin addition or the CRISPR-Cas9 reactivation units alone, in vivo HSC transduction of CD46/Townes mice with the HDAd-combo resulted in significantly higher γ-globin in red blood cells, reaching 30% of that of adult human α and βS chains and a complete phenotypic correction of sickle cell disease.
|
| 巻・号 |
29(2)
|
| ページ |
822-837
|
| 公開日 |
2021-2-3
|
| DOI |
10.1016/j.ymthe.2020.09.001
|
| PII |
S1525-0016(20)30458-5
|
| PMID |
32949495
|
| PMC |
PMC7854285
|
| MeSH |
Adenoviridae / genetics*
Anemia, Sickle Cell / genetics*
Anemia, Sickle Cell / therapy*
Animals
Disease Models, Animal
Genetic Therapy* / methods
Genetic Vectors / genetics*
Hematopoietic Stem Cell Transplantation* / methods
Hematopoietic Stem Cells / metabolism*
Humans
Mice
Transgenes
|
| IF |
8.986
|
| リソース情報 |
| ヒト・動物細胞 |
HUDEP-2(RCB4557) |
