| First Author | Li C | Year | 2021 |
| Journal | Mol Ther | Volume | 29 |
| Issue | 2 | Pages | 822-837 |
| PubMed ID | 32949495 | Mgi Jnum | J:354970 |
| Mgi Id | MGI:7736838 | Doi | 10.1016/j.ymthe.2020.09.001 |
| Citation | Li C, et al. (2021) In Vivo HSC Gene Therapy Using a Bi-modular HDAd5/35++ Vector Cures Sickle Cell Disease in a Mouse Model. Mol Ther 29(2):822-837 |
| abstractText | We have recently reported that, after in vivo hematopoietic stem cell/progenitor (HSPC) transduction with HDAd5/35++ vectors, SB100x transposase-mediated gamma-globin gene addition achieved 10%-15% gamma-globin of adult mouse globin, resulting in significant but incomplete phenotypic correction in a thalassemia intermedia mouse model. Furthermore, genome editing of a gamma-globin repressor binding site within the gamma-globin promoter by CRISPR-Cas9 results in efficient reactivation of endogenous gamma-globin. Here, we aimed to combine these two mechanisms to obtain curative levels of gamma-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/beta-YAC mice and in a sickle cell disease mouse model (CD46/Townes). Compared to HDAd vectors containing either the gamma-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 gamma-globin in red blood cells, reaching 30% of that of adult human alpha and beta(S) chains and a complete phenotypic correction of sickle cell disease. |
