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Lentiviral gene therapy for X-linked chronic granulomatous disease

  1. Author:
    Kohn, Donald B [ORCID]
    Booth, Claire
    Kang, Elizabeth M
    Pai, Sung-Yun
    Shaw, Kit L
    Santilli, Giorgia
    Armant, Myriam
    Buckland, Karen F [ORCID]
    Choi, Uimook
    De Ravin, Suk See
    Dorsey, Morna J
    Kuo, Caroline Y
    Leon-Rico, Diego
    Rivat, Christine
    Izotova, Natalia
    Gilmour, Kimberly
    Snell, Katie
    Dip, Jinhua Xu-Bayford
    Darwish, Jinan
    Morris, Emma C [ORCID]
    Terrazas, Dayna
    Wang, Leo D
    Bauser, Christopher A [ORCID]
    Paprotka, Tobias
    Kuhns,Doug
    Gregg, John
    Raymond, Hayley E
    Everett, John K
    Honnet, Geraldine
    Biasco, Luca
    Newburger, Peter E
    Bushman, Frederic D [ORCID]
    Grez, Manuel
    Gaspar, H Bobby
    Williams, David A
    Malech, Harry L
    Galy, Anne
    Thrasher, Adrian J [ORCID]

  2. Author Address

    University of California, Los Angeles, CA, USA. dkohn@mednet.ucla.edu., Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK., Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Boston Children 39;s Hospital, Harvard Medical School, Boston, MA, USA., University of California, San Francisco, CA, USA., University College London Hospitals NHS Foundation Trust, London, UK., City of Hope, Beckman Research Institute, Duarte, CA, USA., Eurofins Genomics Sequencing Europe, Konstanz, Germany., Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA., University of Pennsylvania, Philadelphia, PA, USA., Genethon, Evry, France., University of Massachusetts Medical School, Worcester, MA, USA., Georg-Speyer Haus, Frankfurt, Germany., Orchard Therapeutics, London, UK., Inserm, University of Evry, Universit 233; Paris Saclay Genethon, Evry, France., Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK. a.thrasher@ucl.ac.uk.,
    1. Year: 2020
    2. Date: Jan 27
    3. Epub Date: 2020 01 27
  2. Journal: Nature medicine
    1. Pages: pii: 10.1038/s41591-019-0735-5
  4. Type of Article: Article
  5. ISSN: 1078-8956
  1. Abstract:

    Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells1,2. We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34+ hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12?months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3?months of treatment from pre-existing comorbidities. At 12?months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4-1.8 copies per neutrophil) and the persistence of 16-46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12?months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients.

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External Sources

  1. View Full Text
  2. DOI: 10.1038/s41591-019-0735-5
  3. PMID: 31988463
  4. View record in Web of Science®
  5. WOS: 000510552300001
  6. PII : 10.1038/s41591-019-0735-5

Library Notes

  1. Fiscal Year: FY2019-2020
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