title: Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial.
abstract: The first human gene therapy experiment begun in September 1990 used a retroviral vector containing the human adenosine deaminase (ADA) cDNA to transduce mature peripheral blood lymphocytes from patients with ADA deficiency, an inherited disorder of immunity. Two patients who had been treated with intramuscular injections of pegylated bovine ADA (PEG-ADA) for 2 to 4 years were enrolled in this trial and each received a total of approximately 10(11) cells in 11 or 12 infusions over a period of about 2 years. No adverse events were observed. During and after treatment, the patients continued to receive PEG-ADA, although at a reduced dose. Ten years after the last cell infusion, approximately 20% of the first patient's lymphocytes still carry and express the retroviral gene, indicating that the effects of gene transfer can be remarkably long lasting. On the contrary, the persistence of gene-marked cells is very low (< 0.1%), and no expression of the transgene is detectable in lymphocytes from the second patient who developed persisting antibodies to components of the gene transfer system. Data collected from these original patients have provided novel information about the longevity of T lymphocytes in humans and persistence of gene expression in vivo from vectors driven by the Moloney murine leukemia virus long-terminal repeat (LTR) promoter. This long-term follow-up has also provided unique evidence supporting the safety of retroviral-mediated gene transfer and illustrates clear examples of both the potential and the pitfalls of gene therapy in humans.
authors.affiliation: Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. muul1@mail.nih.gov
authors.forename: Linda Mesler
authors.initials: LM
authors.lastname: Muul
authors.forename: Laura M
authors.initials: LM
authors.lastname: Tuschong
authors.forename: Sherry Lau
authors.initials: SL
authors.lastname: Soenen
authors.forename: G Jayashree
authors.initials: GJ
authors.lastname: Jagadeesh
authors.forename: W Jay
authors.initials: WJ
authors.lastname: Ramsey
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Long
authors.forename: Charles S
authors.initials: CS
authors.lastname: Carter
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Garabedian
authors.forename: Melinna
authors.initials: M
authors.lastname: Alleyne
authors.forename: Margaret
authors.initials: M
authors.lastname: Brown
authors.forename: Wendy
authors.initials: W
authors.lastname: Bernstein
authors.forename: Shepherd H
authors.initials: SH
authors.lastname: Schurman
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: Susan F
authors.initials: SF
authors.lastname: Leitman
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Dunbar
authors.forename: R Michael
authors.initials: RM
authors.lastname: Blaese
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
mesh_terms: D000243:Adenosine Deaminase / Q000008:administration & dosage / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D000910:Antibodies, Heterophile / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation; D002417:Cattle; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000276:immunology; D006801:Humans; D008137:Longitudinal Studies; D008979:Moloney murine leukemia virus / Q000235:genetics / Q000276:immunology; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000910:Antibodies, Heterophile; D000914:Antibodies, Viral; D011948:Receptors, Antigen, T-Cell; D000243:Adenosine Deaminase; C051409:pegademase bovine