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Gene Therapy Progress and Prospects: Noninvasive imaging of gene therapy in living subjects

Gene Therapy volume 11, pages 115–125 (2004)Cite this article

Abstract

Recent progress in the development of noninvasive imaging technologies should allow molecular imaging to play a major role in the field of gene therapy. These tools have recently been validated in gene therapy models for continuous quantitative monitoring of the location(s), magnitude, and time variation of gene delivery and/or expression. This article reviews the use of radionuclide, magnetic resonance, and optical imaging technologies, as they have been used in imaging gene delivery and gene expression for gene therapy applications. The studies published to date lend support that noninvasive imaging tools will help to accelerate preclinical model validation, as well as allow for clinical monitoring of human gene therapy.

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References

  1. Gambhir SS . Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2002; 2: 683–693.

    CAS  PubMed  Google Scholar 

  2. Massoud TF, Gambhir SS . Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev 2003; 17: 545–580.

    CAS  PubMed  Google Scholar 

  3. Bogdanov A, Weissleder R . In vivo imaging of gene delivery and expression. Trends Biotechnol 2002; 20: S11–S18.

    Google Scholar 

  4. Blasberg R . PET imaging of gene expression. Eur J Cancer 2002; 38: 2137–2146.

    CAS  PubMed  Google Scholar 

  5. Blasberg R . Imaging gene expression and endogenous molecular processes: molecular imaging. J Cereb Blood Flow Metab 2002; 22: 1157–1164.

    CAS  PubMed  Google Scholar 

  6. Wunderbaldinger P, Bogdanov A, Weissleder R . New approaches for imaging in gene therapy. Eur J Radiol 2000; 34: 156–165.

    CAS  PubMed  Google Scholar 

  7. Weissleder R, Mahmood U . Molecular imaging. Radiology 2001; 219: 316–333.

    CAS  PubMed  Google Scholar 

  8. Nichol C, Kim EE . Molecular imaging and gene therapy. J Nucl Med 2001; 42: 1368–1374.

    CAS  PubMed  Google Scholar 

  9. Gambhir SS et al. Imaging transgene expression with radionuclide imaging technologies. Neoplasia 2000; 2: 118–138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Allport JR, Weissleder R . In vivo imaging of gene and cell therapies. Exp Hematol 2001; 29: 1237–1246.

    CAS  PubMed  Google Scholar 

  11. Yang M et al. Visualizing gene expression by whole-body fluorescence imaging. Proc Natl Acad Sci USA 2000; 97: 12278–12282.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Jakobs S et al. EGFP and DsRed expressing cultures of Escherichia coli imaged by confocal, two-photon and fluorescence lifetime microscopy. FEBS Lett 2000; 479: 131–135.

    CAS  PubMed  Google Scholar 

  13. Contag CH, Ross BD . It's not just about anatomy: in vivo bioluminescence imaging as an eyepiece into biology. J Magn Reson Imaging 2002; 16: 378–387.

    PubMed  Google Scholar 

  14. Bhaumik S, Gambhir SS . Optical imaging of Renilla luciferase reporter gene expression in living mice. Proc Natl Acad Sci USA 2002; 99: 377–382.

    CAS  PubMed  Google Scholar 

  15. Wu JC, Sundaresan G, Iyer M, Gambhir SS . Noninvasive optical imaging of firefly luciferase reporter gene expression in skeletal muscles of living mice. Mol Ther 2001; 4: 297–306.

    CAS  PubMed  Google Scholar 

  16. Contag CH, Jenkins D, Contag PR, Negrin RS . Use of reporter genes for optical measurements of neoplastic disease in vivo. Neoplasia 2000; 2: 41–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Ntziachristos V, Tung CH, Bremer C, Weissleder R . Fluorescence molecular tomography resolves protease activity in vivo. Nat Med 2002; 8: 757–760.

    CAS  PubMed  Google Scholar 

  18. Weissleder R . Scaling down imaging: molecular mapping of cancer in mice. Nat Rev Cancer 2002; 2: 11–18.

    CAS  PubMed  Google Scholar 

  19. Schellingerhout D, Rainov NG, Breakefield XO, Weissleder R . Quantitation of HSV mass distribution in a rodent brain tumor model. Gene Therapy 2000; 7: 1648–1655.

    CAS  PubMed  Google Scholar 

  20. Murugesan S, Sundaresan G, Gambhir S . In vivo imaging of Tc-99m adenovirus and reporter gene expression in living subjects. Mol Imaging 2003; 2: 288.

    Google Scholar 

  21. Sundaresan G, Murugesan S, Gambhir S . MicroPET imaging of I-124 adenovirus biodistribution and optical imaging of reporter gene expression in living subjects. Mol Imaging 2003; 2: 302.

    Google Scholar 

  22. Bogdanov Jr A, Tung CH, Bredow S, Weissleder R . DNA binding chelates for nonviral gene delivery imaging. Gene Therapy 2001; 8: 515–522.

    CAS  PubMed  Google Scholar 

  23. Harrington KJ et al. Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes. Clin Cancer Res 2001; 7: 243–254.

    CAS  PubMed  Google Scholar 

  24. Harrison Jr LH et al. Gene-modified PA1-STK cells home to tumor sites in patients with malignant pleural mesothelioma. Ann Thorac Surg 2000; 70: 407–411.

    PubMed  Google Scholar 

  25. Adonai N et al. Ex vivo cell labeling with 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography. Proc Natl Acad Sci USA 2002; 99: 3030–3035.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Le LQ et al. Positron emission tomography imaging analysis of G2A as a negative modifier of lymphoid leukemogenesis initiated by the BCR-ABL oncogene. Cancer Cell 2002; 1: 381–391.

    CAS  PubMed  Google Scholar 

  27. Ponomarev V et al. Imaging TCR-dependent NFAT-mediated T-cell activation with positron emission tomography in vivo. Neoplasia 2001; 3: 480–488.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Dubey P et al. Quantitative imaging of the T cell antitumor response by positron-emission tomography. Proc Natl Acad Sci USA 2003; 100: 1232–1237.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Koehne G et al. Serial in vivo imaging of the targeted migration of human HSV-TK-transduced antigen-specific lymphocytes. Nat Biotechnol 2003; 21: 405–413.

    CAS  PubMed  Google Scholar 

  30. Modo M et al. Tracking transplanted stem cell migration using bifunctional, contrast agent-enhanced, magnetic resonance imaging. Neuroimage 2002; 17: 803–811.

    PubMed  Google Scholar 

  31. Lewin M et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat Biotechnol 2000; 18: 410–414.

    CAS  PubMed  Google Scholar 

  32. Weninger W, Manjunath N, Von Andrian UH . Migration and differentiation of CD8+ T cells. Immunol Rev 2002; 186: 221–233.

    CAS  PubMed  Google Scholar 

  33. Hardy J et al. Bioluminescence imaging of lymphocyte trafficking in vivo. Exp Hematol 2001; 29: 1353–1360.

    CAS  PubMed  Google Scholar 

  34. Ray P et al. Monitoring gene therapy with reporter gene imaging. Semin Nucl Med 2001; 31: 312–320.

    CAS  PubMed  Google Scholar 

  35. Min JJ, Iyer M, Gambhir SS . Comparison of FHBG and FIAU for imaging of HSV1-tk reporter gene expression: adenoviral infection versus stable transfection. Eur J Nucl Med Mol Imaging 2003; 30: 1547–1560.

    CAS  PubMed  Google Scholar 

  36. Tjuvajev JG et al. Comparison of radiolabeled nucleoside probes (FIAU, FHBG, and FHPG) for PET imaging of HSV1-tk gene expression. J Nucl Med 2002; 43: 1072–1083.

    PubMed  Google Scholar 

  37. Herschman HR . Micro-PET imaging and small animal models of disease. Curr Opin Immunol 2003; 15: 378–384.

    CAS  PubMed  Google Scholar 

  38. Zinn KR, Chaudhuri TR . The type 2 human somatostatin receptor as a platform for reporter gene imaging. Eur J Nucl Med Mol Imaging 2002; 29: 388–399.

    CAS  PubMed  Google Scholar 

  39. Chung JK . Sodium iodide symporter: its role in nuclear medicine. J Nucl Med 2002; 43: 1188–1200.

    CAS  PubMed  Google Scholar 

  40. Spitzweg C, Morris JC . The sodium iodide symporter: its pathophysiological and therapeutic implications. Clin Endocrinol (Oxf) 2002; 57: 559–574.

    CAS  Google Scholar 

  41. Haberkorn U, Altmann A, Eisenhut M . Functional genomics and proteomics – the role of nuclear medicine. Eur J Nucl Med Mol Imaging 2002; 29: 115–132.

    CAS  PubMed  Google Scholar 

  42. Liang Q et al. Noninvasive, quantitative imaging in living animals of a mutant dopamine D2 receptor reporter gene in which ligand binding is uncoupled from signal transduction. Gene Therapy 2001; 8: 1490–1498.

    CAS  PubMed  Google Scholar 

  43. Gambhir SS et al. A mutant herpes simplex virus type 1 thymidine kinase reporter gene shows improved sensitivity for imaging reporter gene expression with positron emission tomography. Proc Natl Acad Sci USA 2000; 97: 2785–2790.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Jacobs A et al. Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Lancet 2001; 358: 727–729.

    CAS  PubMed  Google Scholar 

  45. Haberkorn U et al. Enhanced iodide transport after transfer of the human sodium iodide symporter gene is associated with lack of retention and low absorbed dose. Gene Therapy 2003; 10: 774–780.

    CAS  PubMed  Google Scholar 

  46. Cho JY et al. In vivo imaging and radioiodine therapy following sodium iodide symporter gene transfer in animal model of intracerebral gliomas. Gene Therapy 2002; 9: 1139–1145.

    CAS  PubMed  Google Scholar 

  47. Min JJ et al. In vitro and in vivo characteristics of a human colon cancer cell line, SNU-C5N, expressing sodium-iodide symporter. Nucl Med Biol 2002; 29: 537–545.

    CAS  PubMed  Google Scholar 

  48. Groot-Wassink T et al. Adenovirus biodistribution and noninvasive imaging of gene expression in vivo by positron emission tomography using human sodium/iodide symporter as reporter gene. Hum Gene Ther 2002; 13: 1723–1735.

    CAS  PubMed  Google Scholar 

  49. Ray P, Wu AM, Gambhir SS . Optical bioluminescence and positron emission tomography imaging of a novel fusion reporter gene in tumor xenografts of living mice. Cancer Res 2003; 63: 1160–1165.

    CAS  PubMed  Google Scholar 

  50. Richard JC et al. Imaging pulmonary gene expression with positron emission tomography (PET). Am J Respir Crit Care Med 2002; 167: 1257–1263.

    PubMed  Google Scholar 

  51. Ray P, Min JJ, Gambhir S . Multimodality imaging of reporter gene expression in single cells and living mice using a novel triple fusion vector. J Nucl Med 2003; 44: 30.

    Google Scholar 

  52. Liang Q et al. Noninvasive, repetitive, quantitative measurement of gene expression from bicistronic message by positron emission tomography, following gene transfer with adenovirus. Mol Ther 2002; 6.

    CAS  PubMed  Google Scholar 

  53. Yu Y et al. Quantification of target gene expression by imaging reporter gene expression in living animals. Nat Med 2000; 6: 933–937.

    CAS  PubMed  Google Scholar 

  54. Wang YL et al. New approaches for linking PET & therapeutic reporter gene expression for imaging gene therapy with increased sensitivity. J Nucl Med 2001; 42: 75.

    Google Scholar 

  55. Zinn KR et al. Gamma camera dual imaging with a somatostatin receptor and thymidine kinase after gene transfer with a bicistronic adenovirus in mice. Radiology 2002; 223: 417–425.

    CAS  PubMed  Google Scholar 

  56. Hemminki A et al. In vivo molecular chemotherapy and noninvasive imaging with an infectivity-enhanced adenovirus. J Natl Cancer Inst 2002; 94: 741–749.

    CAS  PubMed  Google Scholar 

  57. Sun X et al. Quantitative imaging of gene induction in living animals. Gene Therapy 2001; 8: 1572–1579.

    CAS  PubMed  Google Scholar 

  58. Yaghoubi SS et al. Direct correlation between positron emission tomographic images of two reporter genes delivered by two distinct adenoviral vectors. Gene Therapy 2001; 8: 1072–1080.

    CAS  PubMed  Google Scholar 

  59. Doubrovin M et al. Imaging transcriptional regulation of p53-dependent genes with positron emission tomography in vivo. Proc Natl Acad Sci USA 2001; 98: 9300–9305.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Iyer M et al. Two-step transcriptional amplification as a method for imaging reporter gene expression using weak promoters. Proc Natl Acad Sci USA 2001; 98: 14595–14600.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Iyer M et al. Two step transcriptional amplification (TSTA) for enhancing HSV1-sr39tk reporter gene expression using a new single vector feedback strategy. J Nucl Med 2002; 43: 68.

    Google Scholar 

  62. Qiao J et al. Tumor-specific transcriptional targeting of suicide gene therapy. Gene Therapy 2002; 9: 168–175.

    CAS  PubMed  Google Scholar 

  63. Zhang L et al. Molecular engineering of a two-step transcription amplification (TSTA) system for transgene delivery in prostate cancer. Mol Ther 2002; 5: 223–232.

    CAS  PubMed  Google Scholar 

  64. Zhang L et al. Interrogating androgen receptor function in recurrent prostate cancer. Cancer Res 2003; 63: 4552–4560.

    CAS  PubMed  Google Scholar 

  65. Sato M et al. Optimization of adenoviral vectors to direct highly amplified prostate-specific expression for imaging and gene therapy. Mol Ther 2003; 8: 726–737.

    CAS  PubMed  Google Scholar 

  66. Bennett JJ et al. Positron emission tomography imaging for herpes virus infection: implications for oncolytic viral treatments of cancer. Nat Med 2001; 7: 859–863.

    CAS  PubMed  Google Scholar 

  67. Jacobs A et al. Positron emission tomography-based imaging of transgene expression mediated by replication-conditional, oncolytic herpes simplex virus type 1 mutant vectors in vivo. Cancer Res 2001; 61: 2983–2995.

    CAS  PubMed  Google Scholar 

  68. Weissleder R et al. In vivo magnetic resonance imaging of transgene expression. Nat Med 2000; 6: 351–355.

    CAS  PubMed  Google Scholar 

  69. Moore A et al. Human transferrin receptor gene as a marker gene for MR imaging. Radiology 2001; 221: 244–250.

    CAS  PubMed  Google Scholar 

  70. Ichikawa T et al. MRI of transgene expression: correlation to therapeutic gene expression. Neoplasia 2002; 4: 523–530.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Louie AH et al. In vivo visualization of gene expression using magnetic resonance imaging. Nat Biotechnol 2000; 18: 321–325.

    CAS  PubMed  Google Scholar 

  72. Stegman LD et al. Diffusion MRI detects early events in the response of a glioma model to the yeast cytosine deaminase gene therapy strategy. Gene Therapy 2000; 7: 1005–1010.

    CAS  PubMed  Google Scholar 

  73. Pfeifer A et al. Transduction of liver cells by lentiviral vectors: analysis in living animals by fluorescence imaging. Mol Ther 2001; 3: 319–322.

    CAS  PubMed  Google Scholar 

  74. Tsui LV et al. Production of human clotting Factor IX without toxicity in mice after vascular delivery of a lentiviral vector. Nat Biotechnol 2002; 20: 53–57.

    CAS  PubMed  Google Scholar 

  75. Adams JY et al. Visualization of advanced human prostate cancer lesions in living mice by a targeted gene transfer vector and optical imaging. Nat Med 2002; 8: 891–897.

    CAS  PubMed  Google Scholar 

  76. Iyer M, Berenji M, Templeton NS, Gambhir SS . Noninvasive imaging of cationic lipid-mediated delivery of optical and PET reporter genes in living mice. Mol Ther 2002; 6: 555–562.

    CAS  PubMed  Google Scholar 

  77. Hildebrandt IJ, Iyer M, Wagner E, Gambhir SS . Optical imaging of transferrin targeted PEI/DNA complexes in living subjects. Gene Therapy 2003; 10: 758–764.

    CAS  PubMed  Google Scholar 

  78. Hajjar RJ, del Monte F, Matsui T, Rosenzweig A . Prospects for gene therapy for heart failure. Circ Res 2000; 86: 616–621.

    CAS  PubMed  Google Scholar 

  79. Bengel FM et al. Uptake of radiolabeled 2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabinofuranosyluracil in cardiac cells after adenoviral transfer of the herpesvirus thymidine kinase gene – the cellular basis for cardiac gene imaging. Circulation 2000; 102: 948–950.

    CAS  PubMed  Google Scholar 

  80. Wu JC et al. Optical imaging of cardiac reporter gene expression in living rats. Circulation 2002; 105: 1631–1634.

    PubMed  Google Scholar 

  81. Wu JC et al. Positron emission tomography imaging of cardiac reporter gene expression in living rats. Circulation 2002; 106: 180–183.

    PubMed  PubMed Central  Google Scholar 

  82. Inubushi MWJ et al. PET reporter gene expression imaging in rat myocardium. Circulation 2002; 107: 326–332.

    Google Scholar 

  83. Chen IY et al. MicroPET imaging of cardiac gene expression in rats using bicistronic adenoviral vector-mediated gene delivery. J Nucl Med 2003; 44: 1.

    Google Scholar 

  84. Wu JC et al. Molecular imaging of cardiac cell transplantation in living animals using optical bioluminescence and positron emission tomography. Circulation 2003; 108: 1302–1305.

    PubMed  PubMed Central  Google Scholar 

  85. Bankiewicz KS et al. Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp Neurol 2000; 164: 2–14.

    CAS  PubMed  Google Scholar 

  86. Hoehn M et al. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat. Proc Natl Acad Sci USA 2002; 99: 16267–16272.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Bohnen NI et al. Use of indium-111-labeled hepatocytes to determine the biodistribution of transplanted hepatocytes through portal vein infusion. Clin Nucl Med 2000; 25: 447–450.

    CAS  PubMed  Google Scholar 

  88. Colombo FR et al. Biodistribution studies of 99mTc-labeled myoblasts in a murine model of muscular dystrophy. Nucl Med Biol 2001; 28: 935–940.

    CAS  PubMed  Google Scholar 

  89. Walter G, Barton ER, Sweeney HL . Noninvasive measurement of gene expression in skeletal muscle. Proc Natl Acad Sci USA 2000; 97: 5151–5155.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Auricchio A, Zhou R, Wilson JM, Glickson JD . In vivo detection of gene expression in liver by 31P nuclear magnetic resonance spectroscopy employing creatine kinase as a marker gene. Proc Natl Acad Sci USA 2001; 98: 5205–5210.

    CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Radiology and Bio-X Program, Stanford University, USA

    JJ Min & SS Gambhir

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Min, J., Gambhir, S. Gene Therapy Progress and Prospects: Noninvasive imaging of gene therapy in living subjects. Gene Ther 11, 115–125 (2004). https://doi.org/10.1038/sj.gt.3302191

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