PMID- 20551514
OWN - NLM
STAT- MEDLINE
DCOM- 20100727
LR  - 20211020
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 120
IP  - 7
DP  - 2010 Jul
TI  - Efficient and stable MGMT-mediated selection of long-term repopulating stem cells 
      in nonhuman primates.
PG  - 2345-54
LID - 40767 [pii]
LID - 10.1172/JCI40767 [doi]
AB  - HSC transplantation using genetically modified autologous cells is a promising 
      therapeutic strategy for various genetic diseases, cancer, and HIV. However, for 
      many of these conditions, the current efficiency of gene transfer to HSCs is not 
      sufficient for clinical use. The ability to increase the percentage of 
      gene-modified cells following transplantation is critical to overcoming this 
      obstacle. In vivo selection with mutant methylguanine methyltransferase 
      (MGMTP140K) has been proposed to overcome low gene transfer efficiency to HSCs. 
      Previous studies have shown efficient in vivo selection in mice and dogs but only 
      transient selection in primates. Here, we report efficient and stable 
      MGMTP140K-mediated multilineage selection in both macaque and baboon nonhuman 
      primate models. Treatment consisting of both O6-benzylguanine (O6BG) and 
      N,N'-bis(2-chloroethyl)-N-nitroso-urea (BCNU) stably increased the percentage of 
      transgene-expressing cells from a range of initial levels of engrafted 
      genetically modified cells, with the longest follow-up after drug treatment 
      occurring over 2.2 years. Drug treatment was well tolerated, and selection 
      occurred in myeloid, lymphoid, and erythroid cells as well as platelets. 
      Retrovirus integration site analysis before and after drug treatments confirmed 
      the presence of multiple clones. These nonhuman primate studies closely model a 
      clinical setting and should have broad applications for HSC gene therapy 
      targeting human diseases of malignant, genetic, and infectious nature, including 
      HIV.
FAU - Beard, Brian C
AU  - Beard BC
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, 
      Washington 98109, USA.
FAU - Trobridge, Grant D
AU  - Trobridge GD
FAU - Ironside, Christina
AU  - Ironside C
FAU - McCune, Jeannine S
AU  - McCune JS
FAU - Adair, Jennifer E
AU  - Adair JE
FAU - Kiem, Hans-Peter
AU  - Kiem HP
LA  - eng
GR  - DK077806/DK/NIDDK NIH HHS/United States
GR  - AI061839/AI/NIAID NIH HHS/United States
GR  - P01 HL053750/HL/NHLBI NIH HHS/United States
GR  - P30 DK056465/DK/NIDDK NIH HHS/United States
GR  - DK56465/DK/NIDDK NIH HHS/United States
GR  - P01 AI061839/AI/NIAID NIH HHS/United States
GR  - HL053750/HL/NHLBI NIH HHS/United States
GR  - R21 DK077806/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100614
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 01KC87F8FE (O(6)-benzylguanine)
RN  - 5Z93L87A1R (Guanine)
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
RN  - U68WG3173Y (Carmustine)
SB  - IM
MH  - Animals
MH  - Carmustine
MH  - Genetic Therapy
MH  - Guanine/analogs & derivatives
MH  - Hematopoietic Stem Cell Transplantation
MH  - Macaca nemestrina
MH  - Male
MH  - O(6)-Methylguanine-DNA Methyltransferase/*genetics
MH  - Papio
MH  - Retroviridae/genetics
MH  - Stem Cells
MH  - Transgenes
PMC - PMC2898586
EDAT- 2010/06/17 06:00
MHDA- 2010/07/28 06:00
PMCR- 2010/06/14
CRDT- 2010/06/17 06:00
PHST- 2009/08/07 00:00 [received]
PHST- 2010/04/21 00:00 [accepted]
PHST- 2010/06/17 06:00 [entrez]
PHST- 2010/06/17 06:00 [pubmed]
PHST- 2010/07/28 06:00 [medline]
PHST- 2010/06/14 00:00 [pmc-release]
AID - 40767 [pii]
AID - 10.1172/JCI40767 [doi]
PST - ppublish
SO  - J Clin Invest. 2010 Jul;120(7):2345-54. doi: 10.1172/JCI40767. Epub 2010 Jun 14.