Of the approximately 25,000 genes that comprise the human genome, mutations in more than 1,800 have already been identified as causing hereditary disorders.
Strategies for genetic medicines — that is, therapies that use the transfer of DNA and/or RNA to modify gene expression to compensate for an abnormal phenotype — include the use of somatic stem cells, gene transfer, RNA modification and, in the future, embryonic stem cells.
The main biological barriers to all genetic medicines are delivery and maintenance of the new genetic information. Overcoming these hurdles requires an understanding of: the molecular basis of the disorder, its mode of inheritance, the range of mutations and genotype–phenotype relationships that result in the disease phenotype, how the phenotype is modulated by alternative genes, and how, where and when the disease manifests.
Bone marrow stem cell transplantation from individuals that express the normal gene has been used to treat various inherited diseases, including lysosomal storage disorders, immunodeficiencies, haemoglobinopathies and leukodystrophies.
Gene transfer of the normal gene to an individual affected by a monogenic disorder is an obvious strategy for genetic medicine. Although many mouse (and larger animal) models of hereditary disorders have been 'cured' with gene transfer, in practice, correcting human hereditary disorders has proved to be difficult.
The main thrust in gene-transfer strategies over the next several years will be to develop further: adeno-associated virus vectors for in vivo studies; retrovirus vectors for ex vivo studies that involve autologous haematopoietic stem cells; and probably lentivirus vectors for ex vivo, and possibly in vivo, applications.
RNA-modification therapy targets mRNA, either to suppress mRNA levels, or by correcting or adding function to the mRNA using four basic approaches: antisense oligonucleotides, RNAi, trans-splicing and ribozymes.
Although mouse hereditary disease models have been corrected by RNAi and trans-splicing strategies combined with gene-transfer delivery, low efficiencies and the requirement to effectively treat most affected cells make the successful application to human hereditary disorders a significant challenge.
No genetic medicine has been approved for use in the treatment of any hereditary human disorder, but significant intellectual and economic resources are focused on genetic medicines.
The path of development of ground-breaking therapies that we accept as standard today, such as bone marrow transplantation, monoclonal antibodies, in vitro fertilization and organ transplantation were littered by disappointments; similarly, barriers to success in the development of genetic medicines will be overcome, and we predict that, within 10 to 20 years, doctors of genetic medicine will take their place in the front lines of treating human disease.
The treatment of the more than 1,800 known monogenic hereditary disorders will depend on the development of 'genetic medicines' — therapies that use the transfer of DNA and/or RNA to modify gene expression to correct or compensate for an abnormal phenotype. Strategies include the use of somatic stem cells, gene transfer, RNA modification and, in the future, embryonic stem cells. Despite the efficacy of these technologies in treating experimental models of hereditary disorders, applying them successfully in the clinic is a great challenge, which will only be overcome by expending considerable intellectual and economic resources, and by solving societal concerns about modifications of the human genetic repertoire.
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Treacy, E. P., Valle, D. & Scriver, C. R. in The Metabolic & Molecular Bases of Inherited Disease 8th edn (ed. Scriver, C. R. et al.) 175–192 (McGraw-Hill, New York, 2001).
Rippon, H. J. & Bishop, A. E. Embryonic stem cells. Cell Prolif. 37, 23–34 (2004).
Fischbach, G. D. & Fischbach, R. L. Stem cells: science, policy, and ethics. J. Clin. Invest. 114, 1364–1370 (2004).
Keller, G. Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 19, 1129–1155 (2005).
Hoffman, L. M. & Carpenter, M. K. Characterization and culture of human embryonic stem cells. Nature Biotechnol. 23, 699–708 (2005). This is an excellent review of 'state-of-the-art' human ESC lines. It includes a characterization of markers, expression profiles, directed differentiation strategies and culture conditions for more than 70 published cell lines.
Downing, G. J. & Battey, J. F. Technical assessment of the first 20 years of research using mouse embryonic stem cell lines. Stem Cells 22, 1168–1180 (2004).
Wagers, A. J. & Weissman, I. L. Plasticity of adult stem cells. Cell 116, 639–648 (2004).
Weissman, I. L., Anderson, D. J. & Gage, F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu. Rev. Cell Dev. Biol. 17, 387–403 (2001).
Parkman, R. The application of bone marrow transplantation to the treatment of genetic diseases. Science 232, 1373–1378 (1986).
Krivit, W. Allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal metabolic diseases. Springer Semin. Immunopathol. 26, 119–132 (2004).
Malatack, J. J., Consolini, D. M. & Bayever, E. The status of hematopoietic stem cell transplantation in lysosomal storage disease. Pediatr. Neurol. 29, 391–403 (2003).
Eckfeldt, C. E., Mendenhall, E. M. & Verfaillie, C. M. The molecular repertoire of the 'almighty' stem cell. Nature Rev. Mol. Cell Biol. 6, 2–13 (2005).
Mayhall, E. A., Paffett-Lugassy, N. & Zon, L. I. The clinical potential of stem cells. Curr. Opin. Cell Biol. 16, 713–720 (2004).
Kanazawa, Y. & Verma, I. M. Little evidence of bone marrow-derived hepatocytes in the replacement of injured liver. Proc. Natl Acad. Sci. USA 100 (Suppl. 1), 11850–11853 (2003).
Massengale, M., Wagers, A. J., Vogel, H. & Weissman, I. L. Hematopoietic cells maintain hematopoietic fates upon entering the brain. J. Exp. Med. 201, 1579–1589 (2005).
Anderson, D. J., Gage, F. H. & Weissman, I. L. Can stem cells cross lineage boundaries? Nature Med. 7, 393–395 (2001).
Blaese, R. M. et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science 270, 475–480 (1995).
Crystal, R. G. Transfer of genes to humans: early lessons and obstacles to success. Science 270, 404–410 (1995).
Anderson, W. F. Human gene therapy. Nature 392, 25–30 (1998).
Kaji, E. H. & Leiden, J. M. Gene and stem cell therapies. JAMA 285, 545–550 (2001).
Nott, A., Meislin, S. H. & Moore, M. J. A quantitative analysis of intron effects on mammalian gene expression. RNA 9, 607–617 (2003).
Whitlock, P. R., Hackett, N. R., Leopold, P. L., Rosengart, T. K. & Crystal, R. G. Adenovirus-mediated transfer of a minigene expressing multiple isoforms of VEGF is more effective at inducing angiogenesis than comparable vectors expressing individual VEGF cDNAs. Mol. Ther. 9, 67–75 (2004).
Wilson, J. M. Adenoviruses as gene-delivery vehicles. N. Engl. J. Med. 334, 1185–1187 (1996).
Campbell, E. M. & Hope, T. J. Gene therapy progress and prospects: viral trafficking during infection. Gene Ther. 12, 1353–1359 (2005).
Leopold, P. L. Cell physiology as a variable in gene transfer to endothelium. Curr. Atheroscler. Rep. 5, 171–177 (2003).
Verma, I. M. & Weitzman, M. D. Gene therapy: twenty-first century medicine. Annu. Rev. Biochem. 74, 711–738 (2005).
Lundstrom, K. Latest development in viral vectors for gene therapy. Trends Biotechnol. 21, 117–122 (2003).
Miller, A. D. in Understanding Gene Therapy (ed. Lemoine, N. R.) (Springer, New York, 1999).
Lechardeur, D., Verkman, A. S. & Lukacs, G. L. Intracellular routing of plasmid DNA during non-viral gene transfer. Adv. Drug Deliv. Rev. 57, 755–767 (2005).
Montier, T., et al. Non-viral vectors in cystic fibrosis gene therapy: progress and challenges. Trends Biotechnol. 22, 586–592 (2004).
Thomas, C. E., Ehrhardt, A. & Kay, M. A. Progress and problems with the use of viral vectors for gene therapy. Nature Rev Genet. 4, 346–358 (2003).
Crystal, R. G., et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nature Genet. 8, 42–51 (1994).
Hackett, N. R. & Crystal, R. G. in Gene Therapy (ed. Templeton, N. S. & Lasic, D. D.) 17–40 (Marcel Dekker, New York, 2000).
Wickham, T. J. Targeting adenovirus. Gene Ther. 7, 110–114 (2000).
Dmitriev, I. et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism. J. Virol. 72, 9706–9713 (1998).
Worgall, S. et al. Modification to the capsid of the adenovirus vector that enhances dendritic cell infection and transgene-specific cellular immune responses. J. Virol. 78, 2572–2580 (2004).
Harvey, B. G. et al. Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus. J. Clin. Invest. 104, 1245–1255 (1999).
St George, J. A. Gene therapy progress and prospects: adenoviral vectors. Gene Ther. 10, 1135–1141 (2003).
Kreppel, F. & Kochanek, S. Long-term transgene expression in proliferating cells mediated by episomally maintained high-capacity adenovirus vectors. J. Virol. 78, 9–22 (2004).
Jooss, K. & Chirmule, N. Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy. Gene Ther. 10, 955–963 (2003).
Hackett, N. R., Kaminsky, S. M., Sondhi, D. & Crystal, R. G. Antivector and antitransgene host responses in gene therapy. Curr. Opin. Mol. Ther. 2, 376–382 (2000).
Zabner, J. et al. Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell 75, 207–216 (1993).
Zabner, J. et al. Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis. J. Clin. Invest. 97, 1504–1511 (1996).
Knowles, M. R. et al. A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. N. Engl. J. Med. 333, 823–831 (1995).
Perricone, M. A. et al. Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium. Hum. Gene Ther. 12, 1383–1394 (2001).
Bellon, G. et al. Aerosol administration of a recombinant adenovirus expressing CFTR to cystic fibrosis patients: a phase I clinical trial. Hum. Gene Ther. 8, 15–25 (1997).
Mack, C. A. et al. Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype. Hum. Gene Ther. 8, 99–109 (1997).
Sondhi, D. et al. Feasibility of gene therapy for late neuronal ceroid lipofuscinosis. Arch. Neurol. 58, 1793–1798 (2001).
Raper, S. E. et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol. Genet. Metab 80, 148–158 (2003).
High, K. A. Gene transfer as an approach to treating hemophilia. Semin. Thromb. Hemost. 29, 107–120 (2003).
Crystal, R. G. et al. Analysis of risk factors for local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of comorbid conditions. Hum. Gene Ther. 13, 65–100 (2002).
Freytag, S. O. et al. Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer. Cancer Res. 63, 7497–7506 (2003).
Harvey, B. G. et al. Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. Hum. Gene Ther. 13, 15–63 (2002).
De, D. et al. High levels of persistent expression of α1-antitrypsin mediated by the nonhuman primate serotype rh.10 adeno-associated virus despite preexisting immunity to common human adeno-associated viruses. Mol. Ther. 13, 67–76 (2006).
Gao, G. P. et al. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc. Natl Acad. Sci. USA 99, 11854–11859 (2002). This influential paper was the first to describe the isolation of novel AAV serotypes from rhesus monkeys, and includes an evaluation of the in vivo performance of vectors that were pseudotyped using the capsids from the novel serotypes.
Rabinowitz, J. E. & Samulski, R. J. Building a better vector: the manipulation of AAV virions. Virology 278, 301–308 (2000).
Flotte, T. R. Gene therapy progress and prospects: recombinant adeno-associated virus (rAAV) vectors. Gene Ther. 11, 805–810 (2004).
Conlon, T. J. et al. Efficient hepatic delivery and expression from a recombinant adeno-associated virus 8 pseudotyped α1-antitrypsin vector. Mol. Ther. 12, 867–875 (2005).
Zabner, J. et al. Adeno-associated virus type 5 (AAV5) but not AAV2 binds to the apical surfaces of airway epithelia and facilitates gene transfer. J. Virol. 74, 3852–3858 (2000).
Wang, L. & Herzog, R. W. AAV-mediated gene transfer for treatment of hemophilia. Curr. Gene Ther. 5, 349–360 (2005).
Cheng, S. H. & Smith, A. E. Gene therapy progress and prospects: gene therapy of lysosomal storage disorders. Gene Ther. 10, 1275–1281 (2003).
Wang, L. et al. Sustained correction of disease in naive and AAV2-pretreated hemophilia B dogs: AAV2/8-mediated, liver-directed gene therapy. Blood 105, 3079–3086 (2005).
Passini, M. A. et al. AAV vector-mediated correction of brain pathology in a mouse model of Niemann–Pick A disease. Mol. Ther. 11, 754–762 (2005).
Chao, H., Monahan, P. E., Liu, Y., Samulski, R. J. & Walsh, C. E. Sustained and complete phenotype correction of hemophilia B mice following intramuscular injection of AAV1 serotype vectors. Mol. Ther. 8, 217–222 (2001).
Acland, G. M. et al. Gene therapy restores vision in a canine model of childhood blindness. Nature Genet. 28, 92–95 (2001).
Carter, B. J. Adeno-associated virus vectors in clinical trials. Hum. Gene Ther. 16, 541–550 (2005). This is a concise but comprehensive review of all clinical trials for gene therapy in which AAV vectors were administered, including the route of administration, subject numbers, phase and current status of the trial, and a discussion of the results.
Flotte, T. R. et al. Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: a two-part clinical study. Hum. Gene Ther. 14, 1079–1088 (2003).
Hough, C. & Lillicrap, D. Gene therapy for hemophilia: an imperative to succeed. J. Thromb. Haemost. 3, 1195–1205 (2005).
Duan, D., Yue, Y. & Engelhardt, J. F. Expanding AAV packaging capacity with trans-splicing or overlapping vectors: a quantitative comparison. Mol. Ther. 4, 383–391 (2001).
Pergolizzi, R. G. & Crystal, R. G. Genetic medicine at the RNA level: modifications of the genetic repertoire for therapeutic purposes by pre-mRNA trans-splicing. C. R. Biol. 327, 695–709 (2004).
Biffi, A. & Naldini, L. Gene therapy of storage disorders by retroviral and lentiviral vectors. Hum. Gene Ther. 13, 1133–1142 (2005).
Barquinero, J., Eixarch, H. & Perez-Melgosa, M. Retroviral vectors: new applications for an old tool. Gene. Ther. 11 (Suppl. 1), S3–S9 (2004).
Takeuchi, Y. et al. Type C retrovirus inactivation by human complement is determined by both the viral genome and the producer cell. J. Virol. 68, 8001–8007 (1994).
Grossman, M. et al. Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nature Genet. 6, 335–341 (1994).
Aiuti, A. et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296, 2410–2413 (2002).
Milsom, M. D. & Fairbairn, L. J. Protection and selection for gene therapy in the hematopoietic system. J. Gene Med. 6, 133–146 (2004).
Cavazzana-Calvo, M., Lagresle, C., Hacein-Bey-Abina, S. & Fischer, A. Gene therapy for severe combined immunodeficiency. Annu. Rev. Med. 56, 585–602 (2005).
Muul, L. M. et al. Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial. Blood 101, 2563–2569 (2003).
Kay, M. A., Glorioso, J. C. & Naldini, L. Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nature Med. 7, 33–40 (2001).
Bushman, F. et al. Genome-wide analysis of retroviral DNA integration. Nature Rev Microbiol. 3, 848–858 (2005). An outstanding review of site-selection for genome integration by retroviruses. The data support the surprising conclusion that different retroviruses have different target-site preferences.
Cavazzana-Calvo, M. et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288, 669–672 (2000).
Hacein-Bey-Abina, S. et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302, 415–419 (2003).
Bosch, A., Perret, E., Desmaris, N., Trono, D. & Heard, J. M. Reversal of pathology in the entire brain of mucopolysaccharidosis type VII mice after lentivirus-mediated gene transfer. Hum. Gene Ther. 11, 1139–1150 (2000).
Buchschacher, G. L. & Wong-Staal, F. Development of lentiviral vectors for gene therapy for human diseases. Blood 95, 2499–2504 (2000).
Consiglio, A. et al. In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected mice. Nature Med. 7, 310–316 (2001).
Sadelain, M. et al. Progress toward the genetic treatment of the β-thalassemias. Ann. NY Acad. Sci. 1054, 1–14 (2005).
MacGregor, R. R. Clinical protocol. A phase 1 open-label clinical trial of the safety and tolerability of single escalating doses of autologous CD4 T cells transduced with VRX496 in HIV-positive subjects. Hum. Gene Ther. 12, 2028–2029 (2001).
Zhang, Y. C., Taylor, M. M., Samson, W. K. & Phillips, M. I. Antisense inhibition: oligonucleotides, ribozymes, and siRNAs. Methods Mol. Med. 106, 11–34 (2005).
Crooke, S. T. Progress in antisense technology. Annu. Rev. Med. 55, 61–95 (2004).
Jason, T. L., Koropatnick, J. & Berg, R. W. Toxicology of antisense therapeutics. Toxicol. Appl. Pharmacol. 201, 66–83 (2004).
Wilton, S. D. & Fletcher, S. Antisense oligonucleotides in the treatment of Duchenne muscular dystrophy: Where are we now? Neuromuscul. Disord. 15, 399–402 (2005).
Dykxhoorn, D. M. & Lieberman, J. The silent revolution: RNA interference as basic biology, research tool, and therapeutic. Annu. Rev. Med. 56, 401–423 (2005).
Scherer, L. J. & Rossi, J. J. Approaches for the sequence-specific knockdown of mRNA. Nature Biotechnol. 21, 1457–1465 (2003).
Grimm, D., Pandey, K. & Kay, M. A. Adeno-associated virus vectors for short hairpin RNA expression. Methods Enzymol. 392, 381–405 (2005).
Jackson, A. L. et al. Expression profiling reveals off-target gene regulation by RNAi. Nature Biotechnol. 21, 635–637 (2003).
Harper, S. Q. et al. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc. Natl Acad. Sci. USA 102, 5820–5825 (2005).
Xia, H. et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nature Med. 10, 816–820 (2004). The first demonstration of the efficacy of RNAi gene therapy in a mouse model of an autosomal dominant disorder.
Puttaraju, M., Jamison, S. F., Mansfield, S. G., Garcia-Blanco, M. A. & Mitchell, L. G. Spliceosome-mediated RNA trans-splicing as a tool for gene therapy. Nature Biotechnol. 17, 246–252 (1999).
Chao, H. et al. Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing. Nature Med. 9, 1015–1019 (2003).
Tahara, M. et al. Trans-splicing repair of CD40 ligand deficiency results in naturally regulated correction of a mouse model of hyper-IgM X-linked immunodeficiency. Nature Med. 10, 835–841 (2004).
Liu, X. et al. Partial correction of endogenous ΔF508 CFTR in human cystic fibrosis airway epithelia by spliceosome-mediated RNA trans-splicing. Nature Biotechnol. 20, 47–52 (2002).
Pergolizzi, R. G. et al. In vivo trans-splicing of 5′ and 3′ segments of pre-mRNA directed by corresponding DNA sequences delivered by gene transfer. Mol. Ther. 8, 999–1008 (2003).
Citti, L. & Rainaldi, G. Synthetic hammerhead ribozymes as therapeutic tools to control disease genes. Curr. Gene Ther. 5, 11–24 (2005).
Tanaka, K. et al. Suppression of transthyretin expression by ribozymes: a possible therapy for familial amyloidotic polyneuropathy. J. Neurol. Sci. 183, 79–84 (2001).
Sullivan, J. M., Pietras, K. M., Shin, B. J. & Misasi, J. N. Hammerhead ribozymes designed to cleave all human rod opsin mRNAs which cause autosomal dominant retinitis pigmentosa. Mol. Vis. 8, 102–113 (2002).
Fair, J. H. et al. Correction of factor IX deficiency in mice by embryonic stem cells differentiated in vitro. Proc. Natl Acad. Sci. USA 102, 2958–2963 (2005). Mouse ESCs differentiated in vitro are shown to engraft in the liver sufficiently well to allow the long-term survival of histocompatability mismatched mice that were F9 deficient.
Verlinsky, Y. et al. Human embryonic stem cell lines with genetic disorders. Reprod. Biomed. Online. 10, 105–110 (2005).
Fairchild, P. J., Cartland, S., Nolan, K. F. & Waldmann, H. Embryonic stem cells and the challenge of transplantation tolerance. Trends Immunol. 25, 465–470 (2004).
Martin, M. J., Muotri, A., Gage, F. & Varki, A. Human embryonic stem cells express an immunogenic nonhuman sialic acid. Nature Med. 11, 228–232 (2005).
Hwang, W. S. et al. Patient-specific embryonic stem cells derived from human SCNT blastocysts. Science 308, 1777–1783 (2005).
Kennedy, D. Editorial retraction. Science 311, 335 (2006).
Vats, A., Tolley, N. S., Bishop, A. E. & Polak, J. M. Embryonic stem cells and tissue engineering: delivering stem cells to the clinic. J. R. Soc. Med. 98, 346–350 (2005).
Barberi, T. et al. Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nature Biotechnol. 21, 1200–1207 (2003).
Kim, J. H. et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418, 50–56 (2002).
Bjorklund, L. M. et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc. Natl Acad. Sci. USA 99, 2344–2349 (2002).
Urnov, F. D. et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 435, 646–651 (2005).
High, K. A. Gene therapy: the moving finger. Nature 435, 577–579 (2005).
Desnick, R. J. Enzyme replacement and enhancement therapies for lysosomal diseases. J. Inherit. Metab. Dis. 27, 385–410 (2004).
Spradling, A., Drummond-Barbosa, D. & Kai, T. Stem cells find their niche. Nature 414, 98–104 (2001).
Watt, F. M. & Hogan, B. L. Out of Eden: stem cells and their niches. Science 287, 1427–1430 (2000).
Donovan, P. J. & Gearhart, J. The end of the beginning for pluripotent stem cells. Nature 414, 92–97 (2001).
Wolff, J. A. & Harding, C. O. in Gene Therapy (ed. Templeton, N. S. & Lasic, D. D.) 507–518 (Marcel Dekker, New York, 2000).
Lewin, A. S. et al. Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa. Nature Med. 4, 967–971 (1998).
Vortkamp, A., Gessler, M. & Grzeschik, K. H. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 352, 539–540 (1991).
Crystal, R. G. α1-antitrypsin deficiency, emphysema, and liver disease. Genetic basis and strategies for therapy. J. Clin. Invest. 85, 1343–1352 (1990).
Hofmann, S. L. & Peltonen, L. in The Metabolic & Molecular Bases of Inherited Disease 8th edn (ed. Scriver, C. R. et al.) 3877–3896 (McGraw-Hill, New York, 2001).
Temple, S. The development of neural stem cells. Nature 414, 112–117 (2001).
McKay, R. D. Stem cell biology and neurodegenerative disease. Phil. Trans. R. Soc Lond. B 359, 851–856 (2004).
Kumar, M., Keller, B., Makalou, N. & Sutton, R. E. Systematic determination of the packaging limit of lentiviral vectors. Hum. Gene Ther. 12, 1893–1905 (2001).
Arkin, L. M. et al. Confronting the issues of therapeutic misconception, enrollment decisions, and personal motives in genetic medicine-based clinical research studies for fatal disorders. Hum. Gene Ther. 16, 1028–1036 (2005).
Smith, K. R. Gene therapy: theoretical and bioethical concepts. Arch. Med. Res. 34, 247–268 (2003).
Cornetta, K. & Smith, F. O. Regulatory issues for clinical gene therapy trials. Hum. Gene Ther. 13, 1143–1149 (2002).
Chung, Y. et al. Embryonic and extraembryonic stem cell lines derived from single mouse blastomeres. Nature 439, 216–219 (2006).
Meissner, A. & Jaenisch, R. Generation of nuclear transfer-derived pluripotent ES cells from cloned Cdx2-deficient blastocysts. Nature 439, 212–215 (2006).
Rideout, W. M. III, Hochedlinger, K., Kyba, M., Daley, G. Q. & Jaenisch, R. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell 109, 17–27 (2002).
Roth, D. A., Tawa, N. E., O'Brien, J. M., Treco, D. A. & Selden, R. F. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. N. Engl. J. Med. 344, 1735–1742 (2001).
Caplen, N. J. et al. Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nature Med. 1, 39–46 (1995).
Alton, E. W. et al. Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial. Lancet 353, 947–954 (1999).
Porteous, D. J. et al. Evidence for safety and efficacy of DOTAP cationic liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 4, 210–218 (1997).
Zabner, J. et al. Comparison of DNA-lipid complexes and DNA alone for gene transfer to cystic fibrosis airway epithelia in vivo. J. Clin. Invest. 100, 1529–1537 (1997).
Noone, P. G. et al. Safety and biological efficacy of a lipid-CFTR complex for gene transfer in the nasal epithelium of adult patients with cystic fibrosis. Mol. Ther. 1, 105–114 (2000).
Sorscher, E. J. et al. Gene therapy for cystic fibrosis using cationic liposome mediated gene transfer: a phase I trial of safety and efficacy in the nasal airway. Hum. Gene Ther. 5, 1259–1277 (1994).
Southern, K. W. et al. Repeated nasal administration of liposome-mediated CFTR gene transfer reagents; the clinical and immunological consequences. Pediatr. Pulmonol. 14, A209 (1997).
Stern, M. et al. A double blind placebo controlled trial of pulmonary and nasal administration of liposome-mediated CFTR gene transfer in CF subjects. Am. J. Respir. Crit. Care Med. 157, A564 (1999).
Brigham, K. L. et al. Transfection of nasal mucosa with a normal α1-antitrypsin gene in α1-antitrypsin-deficient subjects: comparison with protein therapy. Hum. Gene Ther. 11, 1023–1032 (2000).
Leone, P. et al. Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann. Neurol. 48, 27–38 (2000).
Romero, N. B. et al. Phase I study of dystrophin plasmid-based gene therapy in Duchenne/Becker muscular dystrophy. Hum. Gene Ther. 15, 1065–1076 (2004).
Bordignon, C. et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science 270, 470–475 (1995).
Onodera, M. et al. Successful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency. Blood 91, 30–36 (1998).
Raper, S. E. et al. Safety and feasibility of liver-directed ex vivo gene therapy for homozygous familial hypercholesterolemia. Ann. Surg. 223, 116–126 (1996).
Dunbar, C. E. et al. 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. 9, 2629–2640 (1998).
Croop, J. M. Gene therapy for fanconi anemia. Curr. Hematol. Rep. 2, 335–340 (2003).
Liu, J. M. et al. Engraftment of hematopoietic progenitor cells transduced with the Fanconi anemia group C gene (FANCC). Hum. Gene Ther. 10, 2337–2346 (1999).
Malech, H. L. et al. Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proc. Natl Acad. Sci. USA 94, 12133–12138 (1997).
Hacein-Bey-Abina, S., Fischer, A. & Cavazzana-Calvo, M. Gene therapy of X-linked severe combined immunodeficiency. Int. J. Hematol. 76, 295–298 (2002).
Bauer, T. R. & Hickstein, D. D. Gene therapy for leukocyte adhesion deficiency. Curr. Opin. Mol. Ther. 2, 383–388 (2000).
Bauer, T. R. et al. Leukocyte adhesion deficiency in children and Irish setter dogs. Pediatr. Res. 55, 363–367 (2004).
O'Shea, J. J. et al. Jak3 and the pathogenesis of severe combined immunodeficiency. Mol. Immunol. 41, 727–737 (2004).
Qiu, X. et al. Implantation of autologous skin fibroblast genetically modified to secrete clotting factor IX partially corrects the hemorrhagic tendencies in two hemophilia B patients. Chin. Med. J. (Engl.) 109, 832–839 (1996).
Powell, J. S. et al. Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion. Blood 102, 2038–2045 (2003).
Harvey, B. G. et al. Variability of human systemic humoral immune responses to adenovirus gene transfer vectors administered to different organs. J. Virol. 73, 6729–6742 (1999).
Hay, J. G., McElvaney, N. G., Herena, J. & Crystal, R. G. Modification of nasal epithelial potential differences of individuals with cystic fibrosis consequent to local administration of a normal CFTR cDNA adenovirus gene transfer vector. Hum. Gene Ther. 6, 1487–1496 (1995).
Raper, S. E. et al. A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum. Gene Ther. 13, 163–175 (2002).
Flotte, T. R., Schwiebert, E. M., Zeitlin, P. L., Carter, B. J. & Guggino, W. B. Correlation between DNA transfer and cystic fibrosis airway epithelial cell correction after recombinant adeno-associated virus serotype 2 gene therapy. Hum. Gene Ther. 16, 921–928 (2005).
Moss, R. B. et al. Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebo-controlled trial. Chest 125, 509–521 (2004).
Wagner, J. A. et al. A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Hum. Gene Ther. 13, 1349–1359 (2002).
Kay, M. A. et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nature Genet. 24, 257–261 (2000).
Janson, C. et al. Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum. Gene Ther. 13, 1391–1412 (2002).
Crystal, R. G. et al. Clinical protocol. Administration of a replication-deficient adeno-associated virus gene transfer vector expressing the human CLN2 cDNA to the brain of children with late infantile neuronal ceroid lipofuscinosis. Hum. Gene Ther. 15, 1131–1154 (2004).
We thank R.G. Pergolizzi, J.L. Boyer, N. Hackett and S. Worgall for helpful discussions. We also thank T. Virgin-Bryan and N. Mohamed for help in preparing this manuscript. The studies described in this article that were carried out by the authors were supported, in part, by the US National Institutes of Health; the Will Rogers Memorial Fund, Los Angeles, California; and The Malcolm Hewitt Wiener Foundation, Greenwich, Connecticut.
The authors declare no competing financial interests.
- Metabolic manipulation
The use of dietary modification or small molecule therapy to compensate for a deranged biological process.
- Protein augmentation
A therapy in which a missing protein is replaced by the administration of a protein that has been purified from mammalian cells/tissues or synthesized as recombinant protein.
An autosomal recessive error of metabolism that is caused by lack of the enzyme that converts phenylalanine to tyrosine. It causes abnormally high phenylalanine levels and severe, progressive mental retardation if untreated, but can be prevented by neonatal screening and a low phenylalanine diet from an early age.
- 'Impeded' androgen therapy
A means to overcome a deficiency in the C1-inhibitor (C1-INH) — a protease inhibitor that is involved in the plasma proteolytic system. The administration of attenuated androgens increases C1-INH expression levels.
- Chemical libraries
Collections of tens or hundreds of thousands of organic chemicals, which are commonly referred to as small molecules, that can be characterized for potential utility in specific conditions using high-throughput screening.
Refers to transplant material that is derived from a genetically independent source. An example is bone marrow transplantation in which the donor and recipient are distinct individuals.
- Neuronal ceroid lipofuscinosis
A group of hereditary, fatal neurodegenerative disorders in which the phenotype is limited to the destruction of the retinal epithelium and the CNS.
A mouse strain that is derived from the transfer of a severe combined immunodeficiency (SCID) mutation onto a non-obese diabetic (NOD) strain background. This strain is an excellent model for testing cell-based therapies with human cells.
- Severe combined immunodeficiency
A family of genetic disorders that affect T-cell differentiation and B-cell immunity, resulting in the absence of a functional immune system.
- Ex vivo gene transfer
A gene-transfer strategy in which the target cells are removed from the individual to be treated, genetically modified in the laboratory, and then administered to the patient.
- In vivo gene transfer
A gene-transfer strategy in which the vector carrying the expression cassette is administered directly to the patient.
- Suicide gene
A gene that encodes a protein that can convert a non-toxic prodrug into a cytotoxic compound.
A condition that is characterized by abnormal skull morphology and digital malformations.
- First generation adenovirus vector
A gene-transfer vector that is based on adenovirus serotype 5 and is characterized by the deletion of the E1 gene, to prevent viral replication, and the E3 gene, to increase cargo space.
- α1-Antitrypsin deficiency
An autosomal recessive disorder that is associated with emphysema and liver disease. It results from the deficiency of a serine protease inhibitor that is produced in the liver and secreted into the plasma, where it inhibits the activity of trypsin and elastase.
- (Viral vector) serotypes
Viral vectors that belong to the same viral family, but that have sufficiently distinct capsids that they can be distinguished by differences in the antibodies that they evoke in vivo, for example, adenovirus serotypes 2 and 5 are group C Adenoviridae.
A gene-transfer strategy that involves the repeated administration of alternating adenovirus vectors that are derived from different serotype subgroups, in order to circumvent anti-adenovirus humoral immunity.
A persistent decrease in the number of blood platelets. It is often associated with haemorrhagic conditions.
Groups of plasma enzymes and regulatory proteins that function in innate immunity and that are activated in a cascading fashion to promote cell lysis.
A subset of tissue cells and extracellular substrates that can house one or more stem cells and control their self-renewal and progeny production in vivo.
An autosomal recessive disorder that presents in infants. The immunodeficiency results from the sensitivity of lymphocytes to the accumulation of adenosine degradation products.
- X-linked SCID
A fatal immunodeficiency disorder that results from mutations in the γc-cytokine receptor. These mutations cause an early block in T and NK lymphocyte differentiation.
A group of related genetic blood disorders that result from mutations in the genes encoding either the α or β-proteins of haemoglobin, which results in anaemia of varying severity.
A highly conserved cytoplasmic enzyme that cleaves dsRNA into small interfering RNAs.
A family of glycoproteins that are produced and secreted by cells of the immune system to boost immune responses to viral infection.
- Hammerhead ribozymes
One of the smallest ribozymes (only 30–40 nt), they are characterized by a structure consisting of three base-paired helices that are connected by two invariant single-stranded regions, which form the catalytic core.
- Familial amyloidotic polyneuropathy
An autosomal dominant disorder that is characterized by deposition of amyloid fibrils in the peripheral nerves and various organs.
- Retinitis pigmentosa
A retinal degeneration disease that results from one of hundreds of mutations in the rhodopsin gene. There are several varieties of this disorder, including both autosomal dominant and autosomal recessive types.
- Zinc-finger nucleases
(ZFNs). Synthetic proteins that are composed of a highly specific DNA-binding domain, which comprises a string of zinc-finger motifs, and a nonspecific DNA-cleaving domain. The combination of ZFNs and DNA repair by homologous recombination represents a strategy of gene correction.
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O'Connor, T., Crystal, R. Genetic medicines: treatment strategies for hereditary disorders. Nat Rev Genet 7, 261–276 (2006). https://doi.org/10.1038/nrg1829
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