Editors' ChoiceGene Therapy

New Advances in Gene Therapy: The Use of MGMTP140K-Mediated Stem Cell Selection in Nonhuman Primates

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Science Translational Medicine  30 Jun 2010:
Vol. 2, Issue 38, pp. 38ec102
DOI: 10.1126/scitranslmed.3001402

The transplantation of allogenic hematopoietic stem cells (HSCs) for the treatment of a variety of diseases has been a tremendous advancement in modern medicine. However, allogenic HSC transplantation is not without its drawbacks. First, many patients do not have suitable donors; second, it is associated with graft-versus-host disease and infectious complications from immunosuppressive therapy. But if host HSCs could be harvested, genetically modified, and then reintroduced (autologous transplantation), these limitations could be overcome. Yet, one major problem to autologous transplantation is the inefficiency of current gene transfer methodology.

Now, Beard et al. have expanded on previous studies in mice and dogs and have shown efficient and stable selection of long-term repopulating stem cells in nonhuman primates using in vivo selection with mutant methylguanine methyltransferase (MGMTP140K). MGMTP140K protects cells from the wild-type MGMT inhibitor O6-benzylguanine (O6BG) in combination with N,N′-bis(2-chloroethyl)-N-nitrosourea (BCNU), and in proof-of-principle experiments the authors tested MGMTP140K-mediated in vivo selection and chemoprotection using gammaretrovirus- and HIV-derived self-inactivating (SIN) lentivirus-based vectors in baboons and macaques. Importantly, not only was the MGMTP140K-mediated in vivo selection process efficient in the monkeys, but the gene-modified cells maintained multilineage hematopoietic repopulation potential over time, and the drug treatment regimen (with O6BG and BCNU) was well tolerated. Moreover, because the selection strategies used by the investigators closely model a clinical setting, they are directly applicable to humans.

Collectively, these studies in mice, dogs, and now nonhuman primates support the use of MGMTP140K-mediated in vivo selection and demonstrate the efficiency of this methodology in the development of new treatments for a broad range of clinical diseases—including various genetic diseases, cancer, and infectious diseases—in which autologous gene-modified cell therapy may be appropriate.

B. C. Beard et al., Efficient and stable MGMT-mediated selection of long-term repopulating stem cells in nonhuman primates. J. Clin. Invest. 14 June 2010 (10.1172/JCI40767). [Abstract]

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