Lentiviral gene therapy for X-linked chronic granulomatous disease recapitulates endogenous CYBB regulation and expression.
Ryan L Wong, Sarah Sackey, Devin Brown, Shantha Senadheera, Katelyn Masiuk, Jason P Quintos, Nicole Colindres, Luke Riggan, Richard A Morgan, Harry L Malech, Roger P Hollis, Donald B Kohn
Author Information
Ryan L Wong: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA. ORCID
Sarah Sackey: Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA. ORCID
Devin Brown: Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Shantha Senadheera: Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Katelyn Masiuk: ImmunoVec, Los Angeles, CA.
Jason P Quintos: ImmunoVec, Los Angeles, CA. ORCID
Richard A Morgan: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Harry L Malech: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. ORCID
Roger P Hollis: Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Donald B Kohn: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA. ORCID
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-CGDmouse 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.
References
Medicine (Baltimore). 2000 May;79(3):170-200
[PMID: 10844936]
