Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency

Suk See De Ravin; Xiaolin Wu; Susan Moir; Lela Kardava; Sandra Anaya-O’Brien; Nana Kwatemaa; Patricia Littel; Narda Theobald; Uimook Choi; Ling Su; Martha Marquesen; Dianne Hilligoss; Janet Lee; Clarissa M. Buckner; Kol A. Zarember; Geraldine O’Connor; Daniel McVicar; Douglas Kuhns; Robert E. Throm; Sheng Zhou; Luigi D. Notarangelo; I. Celine Hanson; Mort J. Cowan; Elizabeth Kang; Coleen Hadigan; Michael Meagher; John T. Gray; Brian P. Sorrentino; Harry L. Malech

doi:10.1126/scitranslmed.aad8856

Research ArticleGene Therapy

Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency

Suk See De Ravin¹,*,
Xiaolin Wu²,
Susan Moir³,
Lela Kardava³,
Sandra Anaya-O’Brien¹,
Nana Kwatemaa¹,
Patricia Littel¹,
Narda Theobald¹,
Uimook Choi¹,
Ling Su²,
Martha Marquesen¹,
Dianne Hilligoss¹,
Janet Lee¹,
Clarissa M. Buckner³,
Kol A. Zarember¹,
Geraldine O’Connor⁴,
Daniel McVicar⁴,
Douglas Kuhns²,
Robert E. Throm⁵,
Sheng Zhou⁵,
Luigi D. Notarangelo⁶,
I. Celine Hanson⁷,
Mort J. Cowan⁸,
Elizabeth Kang¹,
Coleen Hadigan³,
Michael Meagher⁵,
John T. Gray⁹,
Brian P. Sorrentino⁵,† and
Harry L. Malech¹,*,†

¹Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
²Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
³Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
⁴Cancer and Inflammation Program, National Cancer Institute Frederick, Frederick, MD 21702, USA.
⁵Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
⁶Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁷Texas Children’s Hospital, Houston, TX 77030, USA.
⁸Department of Pediatrics, Benioff Children’s Hospital, and University of California, San Francisco, San Francisco, CA, USA.
⁹Audentes Therapeutics, San Francisco, CA 94101, USA.

↵*Corresponding author. E-mail: sderavin{at}niaid.nih.gov (S.S.D.R.); hmalech{at}niaid.nih.gov (H.L.M.)

↵† These authors share co-senior authorship.

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Science Translational Medicine 20 Apr 2016:
Vol. 8, Issue 335, pp. 335ra57
DOI: 10.1126/scitranslmed.aad8856

Suk See De Ravin

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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For correspondence: sderavin@niaid.nih.gov hmalech@niaid.nih.gov

Xiaolin Wu

2Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.

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Susan Moir

3Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.

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Lela Kardava

3Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.

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Sandra Anaya-O’Brien

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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Nana Kwatemaa

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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Patricia Littel

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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Narda Theobald

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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Uimook Choi

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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Ling Su

2Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.

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Martha Marquesen

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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Dianne Hilligoss

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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Janet Lee

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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Clarissa M. Buckner

3Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.

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Kol A. Zarember

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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Geraldine O’Connor

4Cancer and Inflammation Program, National Cancer Institute Frederick, Frederick, MD 21702, USA.

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Daniel McVicar

4Cancer and Inflammation Program, National Cancer Institute Frederick, Frederick, MD 21702, USA.

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Douglas Kuhns

2Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.

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Robert E. Throm

5Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.

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Sheng Zhou

5Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.

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Luigi D. Notarangelo

6Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

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I. Celine Hanson

7Texas Children’s Hospital, Houston, TX 77030, USA.

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Mort J. Cowan

8Department of Pediatrics, Benioff Children’s Hospital, and University of California, San Francisco, San Francisco, CA, USA.

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Elizabeth Kang

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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Coleen Hadigan

3Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.

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Michael Meagher

5Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.

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John T. Gray

9Audentes Therapeutics, San Francisco, CA 94101, USA.

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Brian P. Sorrentino

5Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.

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Harry L. Malech

1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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For correspondence: sderavin@niaid.nih.gov hmalech@niaid.nih.gov

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This article has a correction. Please see:

Erratum for the Research Article: “Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency” by S. S. De Ravin, X. Wu, S. Moir, S. Anaya-O’Brien, N. Kwatemaa, P. Littel, N. Theobald, U. Choi, L. Su, M. Marquesen, D. Hilligoss, J. Lee, C. M. Buckner, K. A. Zarember, G. O’Connor, D. McVicar, D. Kuhns, R. E. Throm, S. Zhou, L. D. Notarangelo, I. C. Hanson, M. J. Cowan, E. Kang, C. Hadigan, M. Meagher, J. T. Gray, B. P. Sorrentino, H. L. Malech - June 01, 2016

SCID gene therapy comes of age

Diseases caused by mutations in single genes are prime candidates for gene therapy. X-linked severe combined immunodeficiency (SCID-X1) patients have mutations in IL2RG, which encodes the common γ chain of several interleukin receptors, resulting in lack of adaptive immune cells. Gene therapy has shown promise in SCID infants but failed in older SCID-X1 children. Now, De Ravin et al. report that lentiviral gene therapy with nonmyeloablative conditioning corrected multiple immune cell types in five older SCID-X1 patients whose symptoms persisted despite undergoing hematopoietic stem cell transplant(s) as infants. Humoral immunity restoration with normal immunoglobulin production and responses to immunization is confirmed in the first two patients with longer follow-up.

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Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency

This article has a correction. Please see:

SCID gene therapy comes of age

Science Translational Medicine

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