title: Anti-human immunodeficiency virus hematopoietic progenitor cell-delivered ribozyme in a phase I study: myeloid and lymphoid reconstitution in human immunodeficiency virus type-1-infected patients.
abstract: A phase I gene transfer clinical study was undertaken to examine the ability to introduce a potential anti-human immunodeficiency virus (HIV) gene therapeutic into hematopoietic progenitor cells (HPC), thereby contributing to multilineage engraftment. The potential therapeutic effect of genetically modifying HPC with protective genes in HIV-infected adults depends in part on the presence of adult thymic activity and myeloid capacity in the setting of HIV replication. Herein we report the presence and expression of a retroviral vector encoding an anti-HIV-1 ribozyme in mature hematopoietic cells of different lineages, and de novo T-lymphocyte development ensuing from genetically engineered CD34(+) HPC. Sustained output of vector-containing mature myeloid and T-lymphoid cells was detected even in patients with multidrug-resistant infection. In addition, the study showed that the degree of persistence of gene-containing cells was dependent on transduced HPC dose. These novel findings support the concept of gene therapy as a modality to effect immune reconstitution with cells engineered to inhibit HIV replication and this report represents the first demonstration of long-term maintenance of a potential therapeutic transgene in HIV disease.
authors.affiliation: Department of Medicine and UCLA AIDS Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Rafael G
authors.initials: RG
authors.lastname: Amado
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Mitsuyasu
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Rosenblatt
authors.forename: Frances K
authors.initials: FK
authors.lastname: Ngok
authors.forename: Andreas
authors.initials: A
authors.lastname: Bakker
authors.forename: Steve
authors.initials: S
authors.lastname: Cole
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chorn
authors.forename: Lii-Shin
authors.initials: LS
authors.lastname: Lin
authors.forename: Gregory
authors.initials: G
authors.lastname: Bristol
authors.forename: Maureen P
authors.initials: MP
authors.lastname: Boyd
authors.forename: Janet L
authors.initials: JL
authors.lastname: MacPherson
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Fanning
authors.forename: Alison V
authors.initials: AV
authors.lastname: Todd
authors.forename: Julie A
authors.initials: JA
authors.lastname: Ely
authors.forename: Jerome A
authors.initials: JA
authors.lastname: Zack
authors.forename: Geoff P
authors.initials: GP
authors.lastname: Symonds
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents; D018952:Antigens, CD34 / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D015658:HIV Infections / Q000276:immunology* / Q000628:therapy; D015497:HIV-1 / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000201:enzymology; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000166:cytology; D016133:Polymerase Chain Reaction; D016337:RNA, Catalytic / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D018952:Antigens, CD34; D016337:RNA, Catalytic