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

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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 Bone marrow CD34+ cells were harvested after enzyme replacement therapy (ERT) was withdrawn; following transduction of ADA cDNA by the γ-retroviral vector GCsapM-ADA, they were administered intravenously.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.

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Acknowledgments

We would like to thank both patients and both families for their cooperation. We are also grateful to the doctors, nurses, and other co-medical staff members who have supported them and this study in many ways. We thank W. Jay Ramsey, Laura Tuschong, G. Jayashree Jagadeesh, and Linda Muul in the Clinical Gene Therapy Branch of the National Human Genome Research Institute, NIH, for the production of clinical-grade GCsapM-ADA supernatant. This work was supported by grants from the Ministry of Health, Labor and Welfare.

Conflict of Interest

The authors have no conflict of interest in relation to this article to disclose.

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Authors and Affiliations

  1. Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Makoto Otsu

  2. Department of Pediatrics, Hokkaido University Graduate School of Medicine, N-15, W-7, Kita-ku, 060-8638, Sapporo, Japan

    Masafumi Yamada, Norikazu Hatano, Nariaki Toita, Shunichiro Takezaki, Yuka Okura, Ryoji Kobayashi, Yoshinori Matsumoto, Nobuaki Kawamura, Yukio Sakiyama & Tadashi Ariga

  3. Research Group of Human Gene Therapy, Hokkaido University Graduate School of Medicine, Hokkaido, Japan

    Makoto Otsu, Satoru Nakajima, Miyuki Kida, Yoshihiro Maeyama, Yukio Sakiyama & Tadashi Ariga

  4. Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan

    Osamu Tatsuzawa & Masafumi Onodera

  5. Department of Cell Transplantation & Regenerative Medicine, Tokai University School of Medicine, Kanagawa, Japan

    Fumiko Tsuchida & Shunichi Kato

  6. Takara Bio, Shiga, Japan

    Masanari Kitagawa & Junichi Mineno

  7. Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA

    Michael S. Hershfield & Pawan Bali

  8. Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Fabio Candotti

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  1. Makoto Otsu
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  2. Masafumi Yamada
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Correspondence to Tadashi Ariga.

Additional information

Norikazu Hatano and Yoshinori Matsumoto are deceased.

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Otsu, M., Yamada, M., Nakajima, S. et al. Outcomes in Two Japanese Adenosine Deaminase-Deficiency Patients Treated by Stem Cell Gene Therapy with No Cytoreductive Conditioning. J Clin Immunol 35, 384–398 (2015). https://doi.org/10.1007/s10875-015-0157-1

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