Advertisement

Pluripotent stem cells and gene therapy

  • Pavel Simara
    Affiliations
    Department of Medicine and Stem Cell Institute, University of Minnesota, Minneapolis, Minn

    Masaryk University, Faculty of Informatics, Centre for Biomedical Image Analysis, Brno, Czech Republic

    International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
    Search for articles by this author
  • Jason A. Motl
    Affiliations
    Department of Medicine and Stem Cell Institute, University of Minnesota, Minneapolis, Minn
    Search for articles by this author
  • Dan S. Kaufman
    Correspondence
    Reprint requests: Dan S. Kaufman, Department of Medicine and Stem Cell Institute, University of Minnesota, MMC 716, Minneapolis, MN 55455
    Affiliations
    Department of Medicine and Stem Cell Institute, University of Minnesota, Minneapolis, Minn

    International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
    Search for articles by this author
Published:January 25, 2013DOI:https://doi.org/10.1016/j.trsl.2013.01.001
      Human pluripotent stem cells represent an accessible cell source for novel cell-based clinical research and therapies. With the realization of induced pluripotent stem cells (iPSCs), it is possible to produce almost any desired cell type from any patient’s cells. Current developments in gene modification methods have opened the possibility for creating genetically corrected human iPSCs for certain genetic diseases that could be used later in autologous transplantation. Promising preclinical studies have demonstrated correction of disease-causing mutations in a number of hematological, neuronal, and muscular disorders. This review aims to summarize these recent advances with a focus on iPSC generation techniques, as well as gene modification methods. We will then further discuss some of the main obstacles remaining to be overcome before successful application of human pluripotent stem cell-based therapy arrives in the clinic and what the future of stem cell research may look like.

      Abbreviations:

      bFGF (basic fibroblast growth factor), dsDNA (double-stranded DNA), ESC (embryonic stem cell), iPSC (induced pluripotent stem cell), hESC (human embryonic stem cell), hiPSC (human induced pluripotent stem cell), mESC (mouse embryonic stem cell), miPSC (mouse induced pluripotent stem cell), OSKM (Oct3/4, Sox2, Klf4, and c-Myc), SCID (severe combined immunodeficiency), STEMCCA (stem cell cassette), TALE (transcription activator-like effector), TALEN (transcription activator-like effector nuclease), ZFN (zinc finger nuclease)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Evans M.J.
        • Kaufman M.H.
        Establishment in culture of pluripotential cells from mouse embryos.
        Nature. 1981; 292: 154-156
        • Martin G.R.
        Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.
        Proc Natl Acad Sci U S A. 1981; 78: 7634-7638
        • Smith A.G.
        • Heath J.K.
        • Donaldson D.D.
        • et al.
        Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides.
        Nature. 1988; 336: 688-690
        • Smith A.G.
        • Hooper M.L.
        Buffalo rat liver cells produce a diffusible activity which inhibits the differentiation of murine embryonal carcinoma and embryonic stem cells.
        Dev Biol. 1987; 121: 1-9
        • Williams R.L.
        • Hilton D.J.
        • Pease S.
        • et al.
        Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells.
        Nature. 1988; 336: 684-687
        • Niwa H.
        • Ogawa K.
        • Shimosato D.
        • Adachi K.
        A parallel circuit of LIF signaling pathways maintains pluripotency of mouse ES cells.
        Nature. 2009; 460: 118-122
        • Thomson J.A.
        • Itskovitz-Eldor J.
        • Shapiro S.S.
        • et al.
        Embryonic stem cell lines derived from human blastocysts.
        Science. 1998; 282: 1145-1147
        • Xu C.
        • Rosler E.
        • Jiang J.
        • et al.
        Basic fibroblast growth factor supports undifferentiated human embryonic stem cell growth without conditioned medium.
        Stem Cells. 2005; 23: 315-323
        • Takahashi K.
        • Yamanaka S.
        Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
        Cell. 2006; 126: 663-676
        • Boland M.J.
        • Hazen J.L.
        • Nazor K.L.
        • et al.
        Adult mice generated from induced pluripotent stem cells.
        Nature. 2009; 461: 91-94
        • Takahashi K.
        • Tanabe K.
        • Ohnuki M.
        • et al.
        Induction of pluripotent stem cells from adult human fibroblasts by defined factors.
        Cell. 2007; 131: 861-872
        • Yu J.
        • Vodyanik M.A.
        • Smuga-Otto K.
        • et al.
        Induced pluripotent stem cell lines derived from human somatic cells.
        Science. 2007; 318: 1917-1920
        • Yamanaka S.
        Induced pluripotent stem cells: past, present, and future.
        Cell Stem Cell. 2012; 10: 678-684
        • Gurdon J.B.
        The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles.
        J Embryol Exp Morphol. 1962; 10: 622-640
        • Wilmut I.
        • Schnieke A.E.
        • McWhir J.
        • Kind A.J.
        • Campbell K.H.
        Viable offspring derived from fetal and adult mammalian cells.
        Nature. 1997; 385: 810-813
        • Tada M.
        • Takahama Y.
        • Abe K.
        • Nakatsuji N.
        • Tada T.
        Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells.
        Curr Biol. 2001; 11: 1553-1558
        • Schneuwly S.
        • Klemenz R.
        • Gehring W.J.
        Redesigning the body plan of drosophila by ectopic expression of the homoeotic gene antennapedia.
        Nature. 1987; 325: 816-818
        • Davis R.L.
        • Weintraub H.
        • Lassar A.B.
        Expression of a single transfected cDNA converts fibroblasts to myoblasts.
        Cell. 1987; 51: 987-1000
        • Stadtfeld M.
        • Hochedlinger K.
        Induced pluripotency: history, mechanisms, and applications.
        Genes Dev. 2010; 24: 2239-2263
        • Ward C.M.
        • Barrow K.M.
        • Stern P.L.
        Significant variations in differentiation properties between independent mouse ES cell lines cultured under defined conditions.
        Exp Cell Res. 2004; 293: 229-238
        • Bock C.
        • Kiskinis E.
        • Verstappen G.
        • et al.
        Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines.
        Cell. 2011; 144: 439-452
        • Guenther M.G.
        • Frampton G.M.
        • Soldner F.
        • et al.
        Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells.
        Cell Stem Cell. 2010; 7: 249-257
        • Newman A.M.
        • Cooper J.B.
        Lab-specific gene expression signatures in pluripotent stem cells.
        Cell Stem Cell. 2010; 7: 258-262
        • Chin M.H.
        • Mason M.J.
        • Xie W.
        • et al.
        Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures.
        Cell Stem Cell. 2009; 5: 111-123
        • Deng J.
        • Shoemaker R.
        • Xie B.
        • et al.
        Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming.
        Nat Biotechnol. 2009; 27: 353-360
        • Doi A.
        • Park I.H.
        • Wen B.
        • et al.
        Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts.
        Nature genetics. 2009; 41: 1350-1353
        • Nishino K.
        • Toyoda M.
        • Yamazaki-Inoue M.
        • et al.
        DNA methylation dynamics in human induced pluripotent stem cells over time.
        PLoS Genet. 2011; 7: e1002085
        • Lister R.
        • Pelizzola M.
        • Kida Y.S.
        • et al.
        Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells.
        Nature. 2011; 471: 68-73
        • Kim K.
        • Doi A.
        • Wen B.
        • et al.
        Epigenetic memory in induced pluripotent stem cells.
        Nature. 2010; 467: 285-290
        • Nichols J.
        • Smith A.
        Naive and primed pluripotent states.
        Cell Stem Cell. 2009; 4: 487-492
        • Silva J.
        • Barrandon O.
        • Nichols J.
        • Kawaguchi J.
        • Theunissen T.W.
        • Smith A.
        Promotion of reprogramming to ground state pluripotency by signal inhibition.
        PLoS Biol. 2008; 6: e253
        • Guo G.
        • Yang J.
        • Nichols J.
        • et al.
        Klf4 reverts developmentally programmed restriction of ground state pluripotency.
        Development. 2009; 136: 1063-1069
        • Marks H.
        • Kalkan T.
        • Menafra R.
        • et al.
        The transcriptional and epigenomic foundations of ground state pluripotency.
        Cell. 2012; 149: 590-604
        • Kim H.
        • Lee G.
        • Ganat Y.
        • et al.
        miR-371-3 expression predicts neural differentiation propensity in human pluripotent stem cells.
        Cell Stem Cell. 2011; 8: 695-706
        • Carey B.W.
        • Markoulaki S.
        • Hanna J.H.
        • et al.
        Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells.
        Cell Stem Cell. 2011; 9: 588-598
        • Hirai H.
        • Tani T.
        • Katoku-Kikyo N.
        • et al.
        Radical acceleration of nuclear reprogramming by chromatin remodeling with the transactivation domain of MyoD.
        Stem Cells. 2011; 29: 1349-1361
        • Sommer C.A.
        • Stadtfeld M.
        • Murphy G.J.
        • Hochedlinger K.
        • Kotton D.N.
        • Mostoslavsky G.
        Induced pluripotent stem cell generation using a single lentiviral stem cell cassette.
        Stem Cells. 2009; 27: 543-549
        • Somers A.
        • Jean J.C.
        • Sommer C.A.
        • et al.
        Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette.
        Stem Cells. 2010; 28: 1728-1740
        • Hacein-Bey-Abina S.
        • Von Kalle C.
        • Schmidt M.
        • et al.
        LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.
        Science. 2003; 302: 415-419
        • Sommer C.A.
        • Sommer A.G.
        • Longmire T.A.
        • et al.
        Excision of reprogramming transgenes improves the differentiation potential of iPS cells generated with a single excisable vector.
        Stem Cells. 2010; 28: 64-74
        • Fusaki N.
        • Ban H.
        • Nishiyama A.
        • Saeki K.
        • Hasegawa M.
        Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome.
        Proc Jpn Acad Ser B Phys Biol Sci. 2009; 85: 348-362
        • Stadtfeld M.
        • Nagaya M.
        • Utikal J.
        • Weir G.
        • Hochedlinger K.
        Induced pluripotent stem cells generated without viral integration.
        Science. 2008; 322: 945-949
        • Harui A.
        • Suzuki S.
        • Kochanek S.
        • Mitani K.
        Frequency and stability of chromosomal integration of adenovirus vectors.
        J Virol. 1999; 73: 6141-6146
        • Okita K.
        • Nakagawa M.
        • Hyenjong H.
        • Ichisaka T.
        • Yamanaka S.
        Generation of mouse induced pluripotent stem cells without viral vectors.
        Science. 2008; 322: 949-953
        • Yu J.
        • Hu K.
        • Smuga-Otto K.
        • et al.
        Human induced pluripotent stem cells free of vector and transgene sequences.
        Science. 2009; 324: 797-801
        • Kim D.
        • Kim C.H.
        • Moon J.I.
        • et al.
        Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins.
        Cell Stem Cell. 2009; 4: 472-476
        • Zhou H.
        • Wu S.
        • Joo J.Y.
        • et al.
        Generation of induced pluripotent stem cells using recombinant proteins.
        Cell Stem Cell. 2009; 4: 381-384
        • Warren L.
        • Manos P.D.
        • Ahfeldt T.
        • et al.
        Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA.
        Cell Stem Cell. 2010; 7: 618-630
        • Capecchi M.R.
        Altering the genome by homologous recombination.
        Science. 1989; 244: 1288-1292
        • Rouet P.
        • Smih F.
        • Jasin M.
        Expression of a site-specific endonuclease stimulates homologous recombination in mammalian cells.
        Proc Natl Acad Sci U S A. 1994; 91: 6064-6068
        • Bibikova M.
        • Beumer K.
        • Trautman J.K.
        • Carroll D.
        Enhancing gene targeting with designed zinc finger nucleases.
        Science. 2003; 300: 764
        • Collin J.
        • Lako M.
        Concise review: putting a finger on stem cell biology: zinc finger nuclease-driven targeted genetic editing in human pluripotent stem cells.
        Stem Cells. 2011; 29: 1021-1033
        • Hockemeyer D.
        • Soldner F.
        • Beard C.
        • et al.
        Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases.
        Nat Biotechnol. 2009; 27: 851-857
        • Lieber M.R.
        The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway.
        Annu Rev Biochem. 2010; 79: 181-211
        • Moynahan M.E.
        • Jasin M.
        Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis.
        Nat Rev Mol Cell Biol. 2010; 11: 196-207
        • Moehle E.A.
        • Rock J.M.
        • Lee Y.L.
        • et al.
        Targeted gene addition into a specified location in the human genome using designed zinc finger nucleases.
        Proc Natl Acad Sci U S A. 2007; 104: 3055-3060
        • Smith J.R.
        • Maguire S.
        • Davis L.A.
        • et al.
        Robust, persistent transgene expression in human embryonic stem cells is achieved with AAVS1-targeted integration.
        Stem Cells. 2008; 26: 496-504
        • Christian M.
        • Cermak T.
        • Doyle E.L.
        • et al.
        Targeting DNA double-strand breaks with TAL effector nucleases.
        Genetics. 2010; 186: 757-761
        • Hockemeyer D.
        • Wang H.
        • Kiani S.
        • et al.
        Genetic engineering of human pluripotent cells using TALE nucleases.
        Nat Biotechnol. 2011; 29: 731-734
        • Mussolino C.
        • Cathomen T.
        TALE nucleases: tailored genome engineering made easy.
        Curr Opin Biotechnol. 2012; 23: 644-650
        • Morbitzer R.
        • Elsaesser J.
        • Hausner J.
        • Lahaye T.
        Assembly of custom TALE-type DNA binding domains by modular cloning.
        Nucleic Acids Res. 2011; 39: 5790-5799
        • Mussolino C.
        • Morbitzer R.
        • Lütge F.
        • Dannemann N.
        • Lahaye T.
        • Cathomen T.
        A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity.
        Nucleic Acids Res. 2011; 39: 9283-9293
        • Perez E.E.
        • Wang J.
        • Miller J.C.
        • et al.
        Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases.
        Nat Biotechnol. 2008; 26: 808-816
        • Richardson C.
        • Jasin M.
        Frequent chromosomal translocations induced by DNA double-strand breaks.
        Nature. 2000; 405: 697-700
        • Daley G.Q.
        The promise and perils of stem cell therapeutics.
        Cell Stem Cell. 2012; 10: 740-749
        • Strauss S.
        Geron trial resumes, but standards for stem cell trials remain elusive.
        Nat Biotechnol. 2010; 28: 989-990
        • Ben-David U.
        • Kopper O.
        • Benvenisty N.
        Expanding the boundaries of embryonic stem cells.
        Cell Stem Cell. 2012; 10: 666-677
        • Schwartz S.D.
        • Hubschman J.P.
        • Heilwell G.
        • et al.
        Embryonic stem cell trials for macular degeneration: a preliminary report.
        Lancet. 2012; 379: 713-720
        • Keirstead H.S.
        • Nistor G.
        • Bernal G.
        • et al.
        Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury.
        J Neurosci. 2005; 25: 4694-4705
        • McDonald J.W.
        • Howard M.J.
        Repairing the damaged spinal cord: a summary of our early success with embryonic stem cell transplantation and remyelination.
        Prog Brain Res. 2002; 137: 299-309
        • Baker M.
        Stem-cell pioneer bows out.
        Nature. 2011; 479: 459
        • Xu X.
        • Qu J.
        • Suzuki K.
        • et al.
        Reprogramming based gene therapy for inherited red blood cell disorders.
        Cell Res. 2012; 22: 941-944
        • Hanna J.
        • Wernig M.
        • Markoulaki S.
        • et al.
        Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin.
        Science. 2007; 318: 1920-1923
        • Sebastiano V.
        • Maeder M.L.
        • Angstman J.F.
        • et al.
        In situ genetic correction of the sickle cell anemia mutation in human induced pluripotent stem cells using engineered zinc finger nucleases.
        Stem Cells. 2011; 29: 1717-1726
        • Wang W.
        Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins.
        Nat Rev Genet. 2007; 8: 735-748
        • Raya A.
        • Rodríguez-Pizà I.
        • Guenechea G.
        • et al.
        Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells.
        Nature. 2009; 460: 53-59
        • Wang Y.
        • Zheng C.G.
        • Jiang Y.
        • et al.
        Genetic correction of β-thalassemia patient-specific iPS cells and its use in improving hemoglobin production in irradiated SCID mice.
        Cell Res. 2012; 22: 637-648
        • Zou J.
        • Sweeney C.L.
        • Chou B.K.
        • et al.
        Oxidase-deficient neutrophils from X-linked chronic granulomatous disease iPS cells: functional correction by zinc finger nuclease-mediated safe harbor targeting.
        Blood. 2011; 117: 5561-5572
        • Soldner F.
        • Laganière J.
        • Cheng A.W.
        • et al.
        Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations.
        Cell. 2011; 146: 318-331
        • An M.C.
        • Zhang N.
        • Scott G.
        • et al.
        Genetic correction of Huntington's disease phenotypes in induced pluripotent stem cells.
        Cell Stem Cell. 2012; 11: 253-263
        • Tedesco F.S.
        • Gerli M.F.
        • Perani L.
        • et al.
        Transplantation of Genetically Corrected Human iPSC-Derived Progenitors in Mice with Limb-Girdle Muscular Dystrophy.
        Sci Transl Med. 2012; 4: 1-13
        • Howden S.E.
        • Gore A.
        • Li Z.
        • et al.
        Genetic correction and analysis of induced pluripotent stem cells from a patient with gyrate atrophy.
        Proc Natl Acad Sci U S A. 2011; 108: 6537-6542
        • Freed C.R.
        • Greene P.E.
        • Breeze R.E.
        • et al.
        Transplantation of embryonic dopamine neurons for severe Parkinson's disease.
        N Engl J Med. 2001; 344: 710-719
        • Mendell J.R.
        • Kissel J.T.
        • Amato A.A.
        • et al.
        Myoblast transfer in the treatment of Duchenne’s muscular dystrophy.
        N Engl J Med. 1995; 333: 832-838
        • Gussoni E.
        • Blau H.M.
        • Kunkel L.M.
        The fate of individual myoblasts after transplantation into muscles of DMD patients.
        Nat Med. 1997; 3: 970-977
        • Blau H.M.
        Cell therapies for muscular dystrophy.
        N Engl J Med. 2008; 359: 1403-1405
        • Kyba M.
        • Perlingeiro R.C.
        • Daley G.Q.
        HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors.
        Cell. 2002; 109: 29-37
        • Zhou Q.
        • Brown J.
        • Kanarek A.
        • Rajagopal J.
        • Melton D.A.
        In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.
        Nature. 2008; 455: 627-632
        • Huang P.
        • He Z.
        • Ji S.
        • et al.
        Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors.
        Nature. 2011; 475: 386-389
        • Ieda M.
        • Fu J.D.
        • Delgado-Olguin P.
        • et al.
        Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors.
        Cell. 2010; 142: 375-386
        • Szabo E.
        • Rampalli S.
        • Risueño R.M.
        • et al.
        Direct conversion of human fibroblasts to multilineage blood progenitors.
        Nature. 2010; 468: 521-526
        • Vierbuchen T.
        • Ostermeier A.
        • Pang Z.P.
        • Kokubu Y.
        • Südhof T.C.
        • Wernig M.
        Direct conversion of fibroblasts to functional neurons by defined factors.
        Nature. 2010; 463: 1035-1041
        • Qian L.
        • Huang Y.
        • Spencer C.I.
        • et al.
        In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes.
        Nature. 2012; 485: 593-598