RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma.
AIDS patients who develop lymphoma are often treated with transplanted hematopoietic progenitor cells. As a first step in developing a hematopoietic cell-based gene therapy treatment, four patients undergoing treatment with these transplanted cells were also given gene-modified peripheral blood-derived (CD34(+)) hematopoietic progenitor cells expressing three RNA-based anti-HIV moieties (tat/rev short hairpin RNA, TAR decoy, and CCR5 ribozyme). In vitro analysis of these gene-modified cells showed no differences in their hematopoietic potential compared with nontransduced cells. In vitro estimates of successful expression of the anti-HIV moieties were initially as high as 22% but declined to approximately 1% over 4 weeks of culture. Ethical study design required that patients be transplanted with both gene-modified and unmanipulated hematopoietic progenitor cells obtained from the patient by apheresis. Transfected cells were successfully engrafted in all four infused patients by day 11, and there were no unexpected infusion-related toxicities. Persistent vector expression in multiple cell lineages was observed at low levels for up to 24 months, as was expression of the introduced small interfering RNA and ribozyme. Therefore, we have demonstrated stable vector expression in human blood cells after transplantation of autologous gene-modified hematopoietic progenitor cells. These results support the development of an RNA-based cell therapy platform for HIV.
DiGiusto
David L
DL
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA.
Krishnan
Amrita
A
Li
Lijing
L
Li
Haitang
H
Li
Shirley
S
Rao
Anitha
A
Mi
Shu
S
Yam
Priscilla
P
Stinson
Sherri
S
Kalos
Michael
M
Alvarnas
Joseph
J
Lacey
Simon F
SF
Yee
Jiing-Kuan
JK
Li
Mingjie
M
Couture
Larry
L
Hsu
David
D
Forman
Stephen J
SJ
Rossi
John J
JJ
Zaia
John A
JA
D000328:Adult; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D015658:HIV Infections / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016483:Lymphoma, AIDS-Related / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D012313:RNA / Q000235:genetics*; D016896:Treatment Outcome
D012313:RNA