Journal of Clinical Immunology

, Volume 35, Issue 4, pp 384–398 | Cite as

Outcomes in Two Japanese Adenosine Deaminase-Deficiency Patients Treated by Stem Cell Gene Therapy with No Cytoreductive Conditioning

  • Makoto Otsu
  • Masafumi Yamada
  • Satoru Nakajima
  • Miyuki Kida
  • Yoshihiro Maeyama
  • Norikazu Hatano
  • Nariaki Toita
  • Shunichiro Takezaki
  • Yuka Okura
  • Ryoji Kobayashi
  • Yoshinori Matsumoto
  • Osamu Tatsuzawa
  • Fumiko Tsuchida
  • Shunichi Kato
  • Masanari Kitagawa
  • Junichi Mineno
  • Michael S. Hershfield
  • Pawan Bali
  • Fabio Candotti
  • Masafumi Onodera
  • Nobuaki Kawamura
  • Yukio Sakiyama
  • Tadashi Ariga
Original Research

Abstract

Objective

We here describe treatment outcomes in two adenosine deaminase (ADA)-deficiency patients (pt) who received stem cell gene therapy (SCGT) with no cytoreductive conditioning. As this protocol has features distinct from those of other clinical trials, its results provide insights into SCGT for ADA deficiency.

Patients and Methods

Pt 1 was treated at age 4.7 years, whereas pt 2, who had previously received T-cell gene therapy, was treated at age 13 years. Bone marrow CD34+ cells were harvested after enzyme replacement therapy (ERT) was withdrawn; following transduction of ADA cDNA by the γ-retroviral vector GCsapM-ADA, they were administered intravenously. No cytoreductive conditioning, at present considered critical for therapeutic benefit, was given before cell infusion. Hematological/immunological reconstitution kinetics, levels of systemic detoxification, gene-marking levels, and proviral insertion sites in hematopoietic cells were assessed.

Results

Treatment was well tolerated, and no serious adverse events were observed. Engraftment of gene-modified repopulating cells was evidenced by the appearance and maintenance of peripheral lymphocytes expressing functional ADA. Systemic detoxification was moderately achieved, allowing temporary discontinuation of ERT for 6 and 10 years in pt 1 and pt 2, respectively. Recovery of immunity remained partial, with lymphocyte counts in pts 1 and 2, peaked at 408/mm3 and 1248/mm3, approximately 2 and 5 years after SCGT. Vector integration site analyses confirmed that hematopoiesis was reconstituted with a limited number of clones, some of which were shown to have myelo-lymphoid potential.

Conclusions

Outcomes in SCGT for ADA-SCID are described in the context of a unique protocol, which used neither ERT nor cytoreductive conditioning. Although proven safe, immune reconstitution was partial and temporary. Our results reiterate the importance of cytoreductive conditioning to ensure greater benefits from SCGT.

Keywords

Gene therapy adenosine deaminase (ADA) severe combined immunodeficiency (SCID) primary immunodeficiency (PID) retroviral vector(s) hematopoietic stem cell(s) 

Supplementary material

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ESM 1(DOCX 34 kb)
10875_2015_157_MOESM2_ESM.pdf (190 kb)
Supplemental Fig 1(PDF 190 kb)
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Supplemental Fig. 2(PDF 257 kb)
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Supplemental Fig. 3(PDF 311 kb)
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Supplemental Fig. 4(PDF 19 kb)
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Supplemental Fig. 5(PDF 174 kb)
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Supplemental Fig. 6(PDF 89 kb)
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Supplemental Fig. 7(PDF 10 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Makoto Otsu
    • 1
    • 3
  • Masafumi Yamada
    • 2
  • Satoru Nakajima
    • 3
  • Miyuki Kida
    • 3
  • Yoshihiro Maeyama
    • 3
  • Norikazu Hatano
    • 2
  • Nariaki Toita
    • 2
  • Shunichiro Takezaki
    • 2
  • Yuka Okura
    • 2
  • Ryoji Kobayashi
    • 2
  • Yoshinori Matsumoto
    • 2
  • Osamu Tatsuzawa
    • 4
  • Fumiko Tsuchida
    • 5
  • Shunichi Kato
    • 5
  • Masanari Kitagawa
    • 6
  • Junichi Mineno
    • 6
  • Michael S. Hershfield
    • 7
  • Pawan Bali
    • 7
  • Fabio Candotti
    • 8
  • Masafumi Onodera
    • 4
  • Nobuaki Kawamura
    • 2
  • Yukio Sakiyama
    • 2
    • 3
  • Tadashi Ariga
    • 2
    • 3
  1. 1.Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical ScienceUniversity of TokyoTokyoJapan
  2. 2.Department of PediatricsHokkaido University Graduate School of MedicineSapporoJapan
  3. 3.Research Group of Human Gene TherapyHokkaido University Graduate School of MedicineHokkaidoJapan
  4. 4.Department of Human GeneticsNational Center for Child Health and DevelopmentTokyoJapan
  5. 5.Department of Cell Transplantation & Regenerative MedicineTokai University School of MedicineKanagawaJapan
  6. 6.Takara BioShigaJapan
  7. 7.Department of BiochemistryDuke University School of MedicineDurhamUSA
  8. 8.Genetics and Molecular Biology Branch, National Human Genome Research InstituteNational Institutes of HealthBethesdaUSA

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