title: Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.
abstract: We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
authors.forename: Kit L
authors.initials: KL
authors.lastname: Shaw
authors.forename: Linda
authors.initials: L
authors.lastname: Muul
authors.forename: Denise
authors.initials: D
authors.lastname: Carbonaro
authors.forename: Robert
authors.initials: R
authors.lastname: Sokolic
authors.forename: Christopher
authors.initials: C
authors.lastname: Choi
authors.forename: Shepherd H
authors.initials: SH
authors.lastname: Schurman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garabedian
authors.forename: Chimene
authors.initials: C
authors.lastname: Kesserwan
authors.forename: G Jayashree
authors.initials: GJ
authors.lastname: Jagadeesh
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Fu
authors.forename: Eric
authors.initials: E
authors.lastname: Gschweng
authors.forename: Aaron
authors.initials: A
authors.lastname: Cooper
authors.forename: John F
authors.initials: JF
authors.lastname: Tisdale
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Weinberg
authors.forename: Gay M
authors.initials: GM
authors.lastname: Crooks
authors.forename: Neena
authors.initials: N
authors.lastname: Kapoor
authors.forename: Ami
authors.initials: A
authors.lastname: Shah
authors.forename: Hisham
authors.initials: H
authors.lastname: Abdel-Azim
authors.forename: Xiao-Jin
authors.initials: XJ
authors.lastname: Yu
authors.forename: Monika
authors.initials: M
authors.lastname: Smogorzewska
authors.forename: Alan S
authors.initials: AS
authors.lastname: Wayne
authors.forename: Howard M
authors.initials: HM
authors.lastname: Rosenblatt
authors.forename: Carla M
authors.initials: CM
authors.lastname: Davis
authors.forename: Celine
authors.initials: C
authors.lastname: Hanson
authors.forename: Radha G
authors.initials: RG
authors.lastname: Rishi
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Gjertson
authors.forename: Otto O
authors.initials: OO
authors.lastname: Yang
authors.forename: Arumugam
authors.initials: A
authors.lastname: Balamurugan
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bauer
authors.forename: Joanna A
authors.initials: JA
authors.lastname: Ireland
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Engel
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Podsakoff
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hershfield
authors.forename: R Michael
authors.initials: RM
authors.lastname: Blaese
authors.forename: Robertson
authors.initials: R
authors.lastname: Parkman
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kohn
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency; D000293:Adolescent; D000361:Agammaglobulinemia / Q000628:therapy*; D018952:Antigens, CD34 / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods*; D002648:Child; D002675:Child, Preschool; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male; D012190:Retroviridae / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000628:therapy*; D014161:Transduction, Genetic; D019172:Transplantation Conditioning; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D000243:Adenosine Deaminase