Abstract
Lentiviral vectors are promising tools for the development of gene therapy since they can transduce both quiescent and dividing target cells. Lentiviral vectors may be particularly promising gene delivery tools for hematopoietic stem cells since these target cells tend to be quiescent and are therefore difficult target cells for vectors that require dividing targets. Human hematopoietic stem cells that can repopulate NOD/SCID mice have been efficiently transduced using HIV-1-based lentiviral vectors and similar vectors can also transduce murine hematopoietic stem cells. HIV-1 vectors that contain strong general promoters can generate high levels of transgene expression and very high expression levels can be generated in erythroid cells in vivo using β-globin regulatory sequences to control the expression of the transgene. Current lentiviral vectors have a similar level of biosafety as oncoretroviral vectors and can therefore theoretically be used in clinical gene therapy protocols. Future challenges include the generation of lentiviral vectors that can express more than one transgene at high levels and the generation of safe permanent packaging cells for practical use in clinical gene therapy trials.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Kohn DB . Gene therapy for haematopoietic and lymphoid disorders Clin Exp Immunol 1997 107 (Suppl. 1): 54–57
Dunbar CE, Kohn DB, Schiffmann R, Barton NW, Nolta JA, Esplin JA, Pensiero M, Long Z, Lockey C, Emmons RV, Csik S, Leitman S, Krebs CB, Carter C, Brady RO, Karlsson S . Retroviral transfer of the glucocerebrosidase gene into CD34+ cells from patients with Gaucher disease: in vivo detection of transduced cells without myeloablation Hum Gene Ther 1998 9: 2629–2640
Sellers SE, Tisdale JF, Agricola BA, Metzger ME, Donahue RE, Dunbar CE, Sorrentino BP . The effect of multidrug-resistance 1 gene versus neo transduction on ex vivo and in vivo expansion of rhesus macaque hematopoietic repopulating cells Blood 2001 97: 1888–1891
Richter J, Karlsson S . Clinical gene therapy in hematology: past and future Int J Hematol 2001 73: 162–169
Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P, Deist FL, Fischer A . Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease Science 2000 288: 669–672
Cheshier SH, Morrison SJ, Liao X, Weissman IL . In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells Proc Natl Acad Sci USA 1999 96: 3120–3125
Gothot A, Pyatt R, McMahel J, Rice S, Srour EF . Functional heterogeneity of human CD34(+) cells isolated in subcompartments of the G0 /G1 phase of the cell cycle Blood 1997 90: 4384–4393
Gothot A, van der Loo JC, Clapp DW, Srour EF . Cell cycle-related changes in repopulating capacity of human mobilized peripheral blood CD34(+) cells in non-obese diabetic/severe combined immune-deficient mice Blood 1998 92: 2641–2649
Miller DG, Adam MA, Miller AD . Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection Mol Cell Biol 1990 10: 4239–4242
Roe T, Reynolds TC, Yu G, Brown PO . Integration of murine leukemia virus DNA depends on mitosis EMBO J 1993 12: 2099–2108
Relander T, Brun A, Hawley RG, Karlsson S, Richter J . Retroviral transduction of human CD34+ cells on fibronectin fragment CH-296 is inhibited by high concentrations of vector containing medium J Gene Med 2001 3: 207–218
Rovira A, De Angioletti M, Camacho-Vanegas O, Liu D, Rosti V, Gallardo HF, Notaro R, Sadelain M, Luzzatto L . Stable in vivo expression of glucose-6-phosphate dehydrogenase (G6PD) and rescue of G6PD deficiency in stem cells by gene transfer Blood 2000 96: 4111–4117
Schilz AJ, Schiedlmeier B, Kuhlcke K, Fruehauf S, Lindemann C, Zeller WJ, Grez M, Fauser AA, Baum C, Eckert HG . MDR1 gene expression in NOD/SCID repopulating cells after retroviral gene transfer under clinically relevant conditions Mol Ther 2000 2: 609–618
Wilpshaar J, Falkenburg JH, Tong X, Noort WA, Breese R, Heilman D, Kanhai H, Orschell-Traycoff CM, Srour EF . Similar repopulating capacity of mitotically active and resting umbilical cord blood CD34(+) cells in NOD/SCID mice Blood 2000 96: 2100–2107
Glimm H, Oh IH, Eaves CJ . Human hematopoietic stem cells stimulated to proliferate in vitro lose engraftment potential during their S/G(2)/M transit and do not reenter G(0) Blood 2000 96: 4185–4193
Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D . In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector Science 1996 272: 263–267
Dull T, Zufferey R, Kelly M, Mandel RJ, Nguyen M, Trono D, Naldini L . A third-generation lentivirus vector with a conditional packaging system J Virol 1998 72: 8463–8471
Miyoshi H, Smith KA, Mosier DE, Verma IM, Torbett BE . Transduction of human CD34+ cells that mediate long-term engraftment of NOD/SCID mice by HIV vectors Science 1999 283: 682–686
Woods NB, Fahlman C, Mikkola H, Hamaguchi I, Olsson K, Zufferey R, Jacobsen SE, Trono D, Karlsson S . Lentiviral gene transfer into primary and secondary NOD/SCID repopulating cells Blood 2000 96: 3725–3733
May C, Rivella S, Callegari J, Heller G, Gaensler KM, Luzzatto L, Sadelain M . Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin Nature 2000 406: 82–86
Sirven A, Ravet E, Charneau P, Zennou V, Coulombel L, Guetard D, Pflumio F, Dubart-Kupperschmitt A . Enhanced transgene expression in cord blood CD34(+)-derived hematopoietic cells, including developing T cells and NOD/SCID mouse repopulating cells, following transduction with modified trip lentiviral vectors Mol Ther 2001 3: 438–448
Emi N, Friedmann T, Yee JK . Pseudotype formation of murine leukemia virus with the G protein of vesicular stomatitis virus J Virol 1991 65: 1202–1207
Akkina RK, Walton RM, Chen ML, Li QX, Planelles V, Chen IS . High-efficiency gene transfer into CD34+ cells with a human immunodeficiency virus type 1-based retroviral vector pseudotyped with vesicular stomatitis virus envelope glycoprotein G J Virol 1996 70: 2581–2585
Klages N, Zufferey R, Trono D . A stable system for the high-titer production of multiply attenuated lentiviral vectors Mol Ther 2000 2: 170–176
Uchida N, Sutton RE, Friera AM, He D, Reitsma MJ, Chang WC, Veres G, Scollay R, Weissman IL . HIV, but not murine leukemia virus, vectors mediate high efficiency gene transfer into freshly isolated G0/G1 human hematopoietic stem cells Proc Natl Acad Sci USA 1998 95: 11939–11944
Case SS, Price MA, Jordan CT, Yu XJ, Wang L, Bauer G, Haas DL, Xu D, Stripecke R, Naldini L, Kohn DB, Crooks GM . Stable transduction of quiescent CD34(+)CD38(−) human hematopoietic cells by HIV-1-based lentiviral vectors Proc Natl Acad Sci USA 1999 96: 2988–2993
Sutton RE, Reitsma MJ, Uchida N, Brown PO . Transduction of human progenitor hematopoietic stem cells by human immunodeficiency virus type 1-based vectors is cell cycle dependent J Virol 1999 73: 3649–3660
Sutton RE, Wu HT, Rigg R, Bohnlein E, Brown PO . Human immunodeficiency virus type 1 vectors efficiently transduce human hematopoietic stem cells J Virol 1998 72: 5781–5788
Mikkola H, Woods NB, Sjogren M, Helgadottir H, Hamaguchi I, Jacobsen SE, Trono D, Karlsson S . Lentivirus gene transfer in murine hematopoietic progenitor cells is compromised by a delay in proviral integration and results in transduction mosaicism and heterogeneous gene expression in progeny cells J Virol 2000 74: 11911–11918
Bukrinsky MI, Haggerty S, Dempsey MP, Sharova N, Adzhubel A, Spitz L, Lewis P, Goldfarb D, Emerman M, Stevenson M . A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells Nature 1993 365: 666–669
Popov S, Rexach M, Zybarth G, Reiling N, Lee MA, Ratner L, Lane CM, Moore MS, Blobel G, Bukrinsky M . viral protein R regulates nuclear import of the HIV-1 pre-integration complex EMBO J 1998 17: 909–917
Freed EO, Englund G, Martin MA . Role of the basic domain of human immunodeficiency virus type 1 matrix in macrophage infection J Virol 1995 69: 3949–3954
Fouchier RA, Meyer BE, Simon JH, Fischer U, Malim MH . HIV-1 infection of non-dividing cells: evidence that the amino-terminal basic region of the viral matrix protein is important for Gag processing but not for post-entry nuclear import EMBO J 1997 16: 4531–4539
Zennou V, Petit C, Guetard D, Nerhbass U, Montagnier L, Charneau P . HIV-1 genome nuclear import is mediated by a central DNA flap Cell 2000 101: 173–185
Follenzi A, Ailles LE, Bakovic S, Geuna M, Naldini L . Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences Nat Genet 2000 25: 217–222
Sirven A, Pflumio F, Zennou V, Titeux M, Vainchenker W, Coulombel L, Dubart-Kupperschmitt A, Charneau P . The human immunodeficiency virus type-1 central DNA flap is a crucial determinant for lentiviral vector nuclear import and gene transduction of human hematopoietic stem cells Blood 2000 96: 4103–4110
Plavec I, Voytovich A, Moss K, Webster D, Hanley MB, Escaich S, Ho KE, Bohnlein E, DiGiusto DL . Sustained retroviral gene marking and expression in lymphoid and myeloid cells derived from transduced hematopoietic progenitor cells Gene Ther 1996 3: 717–724
Douglas J, Kelly P, Evans JT, Garcia JV . Efficient transduction of human lymphocytes and CD34+ cells via human immunodeficiency virus-based gene transfer vectors Hum Gene Ther 1999 10: 935–945
Sastry KJ, Marin MC, Nehete PN, McConnell K, el-Naggar AK, McDonnell TJ . Expression of human immunodeficiency virus type I tat results in down-regulation of bcl-2 and induction of apoptosis in hematopoietic cells Oncogene 1996 13: 487–493
Kruman II, Nath A, Mattson MP . HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress Exp Neurol 1998 154: 276–288
Salmon P, Kindler V, Ducrey O, Chapuis B, Zubler RH, Trono D . High-level transgene expression in human hematopoietic progenitors and differentiated blood lineages after transduction with improved lentiviral vectors Blood 2000 96: 3392–3398
Ramezani A, Hawley TS, Hawley RG . Lentiviral vectors for enhanced gene expression in human hematopoietic cells Mol Ther 2000 2: 458–469
Robbins PB, Yu XJ, Skelton DM, Pepper KA, Wasserman RM, Zhu L, Kohn DB . Increased probability of expression from modified retroviral vectors in embryonal stem cells and embryonal carcinoma cells J Virol 1997 71: 9466–9474
Berkowitz R, Ilves H, Lin WY, Eckert K, Coward A, Tamaki S, Veres G, Plavec I . Construction and molecular analysis of gene transfer systems derived from bovine immunodeficiency virus J Virol 2001 75: 3371–3382
Woods NB, Mikkola H, Nilsson E, Flygare J, Relander T, Richter J, Salmon P, Trono D, Karlsson S . Lentiviral vector design for optimal expression in the progeny of NOD/SCID repopulating cells in vivo Blood 2000 96 (Suppl. 1): 524a
Mikkola H, Helgadottir H, Woods NB, Salmon P, Trono D, Karlsson S . Efficient lentiviral gene transfer into murine hematopoietic stem cells and stable expression of the lentiviral transgene in myeloid and lymphoid cells of serially transplanted mice Blood 2000 96 (Suppl. 1): 588a
Zufferey R, Donello JE, Trono D, Hope TJ . Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors J Virol 1999 73: 2886–2892
Zufferey R, Dull T, Mandel RJ, Bukovsky A, Quiroz D, Naldini L, Trono D . Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery J Virol 1998 72: 9873–9880
Schambach A, Wodrich H, Hildinger M, Bohne J, Krausslich HG, Baum C . Context dependence of different modules for posttranscriptional enhancement of gene expression from retroviral vectors Mol Ther 2000 2: 435–445
Harrich D, Garcia J, Wu F, Mitsuyasu R, Gonazalez J, Gaynor R . Role of SP1-binding domains in in vivo transcriptional regulation of the human immunodeficiency virus type 1 long terminal repeat J Virol 1989 63: 2585–2591
Wakabayashi-Ito N, Nagata S . Characterization of the regulatory elements in the promoter of the human elongation factor-1 alpha gene J Biol Chem 1994 269: 29831–29837
D'Costa J, Brown H, Kundra P, Davis-Warren A, Arya S . Human immunodeficiency virus type 2 lentiviral vectors: packaging signal and splice donor in expression and encapsidation J Gen Virol 2001 82: 425–434
Poeschla EM, Wong-Staal F, Looney DJ . Efficient transduction of nondividing human cells by feline immunodeficiency virus lentiviral vectors Nat Med 1998 4: 354–357
Schnell T, Foley P, Wirth M, Munch J, Uberla K . Development of a self-inactivating, minimal lentivirus vector based on simian immunodeficiency virus Hum Gene Ther 2000 11: 439–447
Yamada K, Olsen JC, Patel M, Rao KW, Walsh CE . Functional correction of fanconi anemia group C hematopoietic cells by the use of a novel lentiviral vector Mol Ther 2001 3: 485–490
Jin L, Zeng H, Chien S, Otto KG, Richard RE, Emery DW, Blau CA . In vivo selection using a cell-growth switch Nat Genet 2000 26: 64–66
Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P . Bone marrow cells regenerate infarcted myocardium Nature 2001 410: 701–705
Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M . Purified hematopoietic stem cells can differentiate into hepatocytes in vivo Nat Med 2000 6: 1229–1234
Hamaguchi I, Woods NB, Panagopoulos I, Andersson E, Mikkola H, Fahlman C, Zufferey R, Carlsson L, Trono D, Karlsson S . Lentivirus vector gene expression during ES cell-derived hematopoietic development in vitro J Virol 2000 74: 10778–10784
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Woods, NB., Ooka, A. & Karlsson, S. Development of gene therapy for hematopoietic stem cells using lentiviral vectors. Leukemia 16, 563–569 (2002). https://doi.org/10.1038/sj.leu.2402447
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2402447
Keywords
This article is cited by
-
Safety profiling of genetically engineered Pim-1 kinase overexpression for oncogenicity risk in human c-kit+ cardiac interstitial cells
Gene Therapy (2019)
-
Peculiarities of Gene Transfer into Mesenchymal Stem Cells
Bulletin of Experimental Biology and Medicine (2015)
-
Imaging Stem Cell-derived Persistent Foci After In Vivo Selection of Lentiviral MGMT-P140K Transduced Murine Bone Marrow Cells
Molecular Therapy (2011)
-
Gene Therapy of Chronic Granulomatous Disease: The Engraftment Dilemma
Molecular Therapy (2011)
-
Characteristics of Mesenchymal Stromal Precursor Cells Labeled with Lentiviral Vector in Long-Term Bone Marrow Culture
Bulletin of Experimental Biology and Medicine (2010)