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.
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.
Amado
Rafael G
RG
Department of Medicine and UCLA AIDS Institute, University of California, Los Angeles, CA 90095, USA.
Mitsuyasu
Ronald T
RT
Rosenblatt
Joseph D
JD
Ngok
Frances K
FK
Bakker
Andreas
A
Cole
Steve
S
Chorn
Nathalie
N
Lin
Lii-Shin
LS
Bristol
Gregory
G
Boyd
Maureen P
MP
MacPherson
Janet L
JL
Fanning
Gregory C
GC
Todd
Alison V
AV
Ely
Julie A
JA
Zack
Jerome A
JA
Symonds
Geoff P
GP
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
D019380:Anti-HIV Agents; D018952:Antigens, CD34; D016337:RNA, Catalytic