| Title: | Outcomes in Two Japanese Adenosine Deaminase-Deficiency Patients Treated by Stem Cell Gene Therapy with No Cytoreductive Conditioning |
| Authors: | Otsu, Makoto Browse this author →KAKEN DB |
| Yamada, Masafumi Browse this author |
| Nakajima, Satoru Browse this author |
| Kida, Miyuki Browse this author →KAKEN DB |
| Maeyama, Yoshihiro Browse this author |
| Hatano, Norikazu Browse this author |
| Toita, Nariaki Browse this author |
| Takezaki, Shunichiro Browse this author |
| Okura, Yuka Browse this author |
| Kobayashi, Ryoji Browse this author |
| Matsumoto, Yoshinori Browse this author |
| Tatsuzawa, Osamu Browse this author |
| Tsuchida, Fumiko Browse this author |
| Kato, Shunichi Browse this author →KAKEN DB |
| Kitagawa, Masanari Browse this author |
| Mineno, Junichi Browse this author |
| Hershfield, Michael S. Browse this author |
| Bali, Pawan Browse this author |
| Candotti, Fabio Browse this author |
| Onodera, Masafumi Browse this author →KAKEN DB |
| Kawamura, Nobuaki Browse this author →KAKEN DB |
| Sakiyama, Yukio Browse this author →KAKEN DB |
| Ariga, Tadashi Browse this author →KAKEN DB |
| Keywords: | Gene therapy |
| adenosine deaminase (ADA) |
| severe combined immunodeficiency (SCID) |
| primary immunodeficiency (PID) |
| retroviral vector(s) |
| hematopoietic stem cell(s) |
| Issue Date: | May-2015 |
| Publisher: | Springer |
| Journal Title: | Journal of clinical immunology |
| Volume: | 35 |
| Issue: | 4 |
| Start Page: | 384 |
| End Page: | 398 |
| Publisher DOI: | 10.1007/s10875-015-0157-1 |
| 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 Bone marrow CD34(+) cells were harvested after enzyme replacement therapy (ERT) was withdrawn; following transduction of ADA cDNA by the gamma-retroviral vector GCsapM-ADA, they were administered intravenously.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/mm(3) and 1248/mm(3), 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. |
| Rights: | The final publication is available at link.springer.com |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/61454 |
| Appears in Collections: | 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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