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Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1

  1. Author:
    Ott, M. G.
    Schmidt, M.
    Schwarzwaelder, K.
    Stein, S.
    Siler, U.
    Koehl, U.
    Glimm, H.
    Kuhlcke, K.
    Schilz, A.
    Kunkel, H.
    Naundorf, S.
    Brinkmann, A.
    Deichmann, A.
    Fischer, M.
    Ball, C.
    Pilz, I.
    Dunbar, C.
    Du, Y.
    Jenkins, N. A.
    Copeland, N. G.
    Luthi, U.
    Hassan, M.
    Thrasher, A. J.
    Hoelzer, D.
    von Kalle, C.
    Seger, R.
    Grez, M.

  2. Author Address

    Inst Biomed Res, D-60596 Frankfurt, Germany. Univ Hosp, Dept Hematol Oncol, D-60590 Frankfurt, Germany. Univ Hosp, Dept Internal Med 1, D-79106 Freiburg, Germany. Univ Freiburg, Inst Mol Med & Cell Res, D-79104 Freiburg, Germany. Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany. Univ Freiburg, Fac Biol, D-79104 Freiburg, Germany. Univ Childrens Hosp, Div Hematol Immunol, CH-8032 Zurich, Switzerland. Univ Hosp, D-60590 Frankfurt, Germany. EUFETS AG, D-55743 Idar Oberstein, Germany. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. Univ Zurich, Cent Lab Electron Microscopy, CH-8006 Zurich, Switzerland. Karolinska Inst, Div Hematol, Dept Med, SE-17177 Stockholm, Sweden. Inst Child Hlth, Mol Immunol Unit, London WC1H 1EH, England. Cincinnati Childrens Res Fdn, Mol & Gene Therapy Program, Cincinnati, OH 45229 USA.;Grez, M, Inst Biomed Res, Georg Speyer Haus,Paul Ehrlich Str 42, D-60596 Frankfurt, Germany.;christof.kalle@nct-heidelberg.de grez@em.uni-frankfurt.de
    1. Year: 2006
    2. Date: Apr
  2. Journal: Nature Medicine
    1. 12
    2. 4
    3. Pages: 401-409
  4. Type of Article: Article
  5. ISSN: 1078-8956
  1. Abstract:

    Gene transfer into hematopoietic stem cells has been used successfully for correcting lymphoid but not myeloid immunodeficiencies. Here we report on two adults who received gene therapy after nonmyeloablative bone marrow conditioning for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes resulting from mutations in gp91(phox). We detected substantial gene transfer in both individuals' neutrophils that lead to a large number of functionally corrected phagocytes and notable clinical improvement. Large-scale retroviral integration site-distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals. Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD.

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  2. DOI: 10.1038/nm1393
  3. View record in Web of Science®
  4. WOS: 000236581300028

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