Details

Autor(en) / Beteiligte

• Wong, Ryan L.
• Sackey, Sarah
• Brown, Devin
• Senadheera, Shantha
• Masiuk, Katelyn
• Quintos, Jason P.
• Colindres, Nicole
• Riggan, Luke
• Morgan, Richard A.
• Malech, Harry L.
• Hollis, Roger P.
• Kohn, Donald B.

Titel

Lentiviral gene therapy for X-linked chronic granulomatous disease recapitulates endogenous CYBB regulation and expression

Ist Teil von

• Blood, 2023-03, Vol.141 (9), p.1007-1022

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• •We used a bioinformatics-guided approach to design a lentiviral vector driven by endogenous enhancer and promoter elements of the CYBB gene.•Our novel vector restores physiologic regulation and expression of CYBB for the treatment of X-CGD. [Display omitted] X-linked chronic granulomatous disease (X-CGD) is a primary immunodeficiency caused by mutations in the CYBB gene, resulting in the inability of phagocytic cells to eliminate infections. To design a lentiviral vector (LV) capable of recapitulating the endogenous regulation and expression of CYBB, a bioinformatics-guided approach was used to elucidate the cognate enhancer elements regulating the native CYBB gene. Using this approach, we analyzed a 600-kilobase topologically associated domain of the CYBB gene and identified endogenous enhancer elements to supplement the CYBB promoter to develop MyeloVec, a physiologically regulated LV for the treatment of X-CGD. When compared with an LV currently in clinical trials for X-CGD, MyeloVec showed improved expression, superior gene transfer to hematopoietic stem and progenitor cells (HSPCs), corrected an X-CGD mouse model leading to complete protection against Burkholderia cepacia infection, and restored healthy donor levels of antimicrobial oxidase activity in neutrophils derived from HSPCs from patients with X-CGD. Our findings validate the bioinformatics-guided design approach and have yielded a novel LV with clinical promise for the treatment of X-CGD. X-linked chronic granulomatous disease is caused by mutations in the CYBB gene, encoding a subunit of the nicotinamide adenine dinucleotide phosphate oxidase complex. It is a target for gene therapy; however, current lentiviral vectors have limited success in reconstituting oxidase activity. Wong et al used bioinformatics to define enhancer elements and create a novel lentiviral vector that mimics physiologic regulation of CYBB. In preclinical studies, the vector showed improved gene transfer and reconstitution of oxidase activity.