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 β chains and a complete phenotypic correction of sickle cell disease.