title: Outcomes in two Japanese adenosine deaminase-deficiency patients treated by stem cell gene therapy with no cytoreductive conditioning.
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.
  
  
  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 Bone marrow CD34(+) cells were harvested after enzyme replacement therapy (ERT) was withdrawn; following transduction of ADA cDNA by the γ-retroviral vector GCsapM-ADA, they were administered intravenously.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/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.
authors: Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors: Makoto
authors: M
authors: Otsu
authors: Masafumi
authors: M
authors: Yamada
authors: Satoru
authors: S
authors: Nakajima
authors: Miyuki
authors: M
authors: Kida
authors: Yoshihiro
authors: Y
authors: Maeyama
authors: Norikazu
authors: N
authors: Hatano
authors: Nariaki
authors: N
authors: Toita
authors: Shunichiro
authors: S
authors: Takezaki
authors: Yuka
authors: Y
authors: Okura
authors: Ryoji
authors: R
authors: Kobayashi
authors: Yoshinori
authors: Y
authors: Matsumoto
authors: Osamu
authors: O
authors: Tatsuzawa
authors: Fumiko
authors: F
authors: Tsuchida
authors: Shunichi
authors: S
authors: Kato
authors: Masanari
authors: M
authors: Kitagawa
authors: Junichi
authors: J
authors: Mineno
authors: Michael S
authors: MS
authors: Hershfield
authors: Pawan
authors: P
authors: Bali
authors: Fabio
authors: F
authors: Candotti
authors: Masafumi
authors: M
authors: Onodera
authors: Nobuaki
authors: N
authors: Kawamura
authors: Yukio
authors: Y
authors: Sakiyama
authors: Tadashi
authors: T
authors: Ariga
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use; D000293:Adolescent; D000361:Agammaglobulinemia / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D017668:Age of Onset; D002454:Cell Differentiation; D002675:Child, Preschool; D004789:Enzyme Activation; D056947:Enzyme Replacement Therapy; D017988:Gammaretrovirus / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007109:Immunity; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D007564:Japan; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D014161:Transduction, Genetic; D019076:Transgenes; D016896:Treatment Outcome
chemical_list: D000243:Adenosine Deaminase; C051409:pegademase bovine