Helper-dependent Adenovirus 3/35++ Encoding CYBB Transgene EN-374

**Semantic type:** Pharmacologic Substance

**Definition:** An off-the-shelf formulation based on helper-dependent adenovirus (HDAd) 3/35++ and composed of two independent virus-like particles (VLPs), one of which contains a transposon with a myeloid-specific promoter expressing wild-type CYBB transgene, with potential immune function restoring activity in the x-linked form of chronic granulomatous disease (CGD). Upon intravenous administration of HDAd3/35++ encoding CYBB transgene EN-374, wild-type CYBB is expressed in hematopoietic stem cells (HSCs) and in neutrophils. This restores nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in neutrophils, which may restore the ability of phagocytic cells to eliminate bacterial and fungal pathogens with reactive oxygen species and the ability to fight infection in patients with the x-linked form of CGD. The x-linked form of CGD is caused by mutations in the CYBB gene. One of the VLPs in EN-374 contains DNA-encoding Sleeping Beauty 100X transposase and Flp recombinase. The other VLP contains a ubiquitous promoter expressing methylguanine methyltransferase (MGMT)-P140K variant in addition to the transposon with a myeloid-specific promoter expressing wild-type CYBB transgene. The MGMT-P140K prevents the binding to O6-benzylguanine (O6BG) and thus the elimination of HSCs gene-modified in vivo with EN-374 by O6BG/Temozolomide (TMZ) during the enrichment phase when unmodified HSCs are depleted.

**Synonyms:** - EN 374 - EN-374 - EN374 - HDAd Encoding CYBB Transgene EN-374 - HDAd3/35++ Encoding CYBB Transgene EN-374