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Demyelination but no cognitive, motor or behavioral deficits after adenovirus-mediated gene transfer into the brain


Adenovirus-mediated gene transfer of interferon gamma (AdIFN) elicits rejection of intracerebral Lewis lung carcinoma. In this system, gene transfer into brain parenchymal cells is both necessary and sufficient to generate the antitumor response. Despite persistent parenchymal inflammation and demyelination, wild-type mice injected intracerebrally with either AdIFN or β-galactosidase adenovirus (AdBGAL) perform as well as non-injected animals in behavioral, memory, and motor tests. Both AdIFN and AdBGAL elicit demyelination whose incidence rises sharply when the lowest effective dose of AdIFN is exceeded. Therefore, transfer of interferon gamma into brain parenchyma does not seem to elicit detectable cognitive, behavioral or motor deficits. Furthermore, gene transfer into the brain, by adenoviral vectors currently in clinical trials, is associated with a narrow therapeutic window where the incidence of demyelination rises sharply soon after the effective dose is achieved.

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  1. Fathallah-Shaykh H . New molecular strategies to cure brain tumors Arch Neurol 1999 56: 449–453

    Article  CAS  Google Scholar 

  2. Fathallah-Shaykh HM, Zhao LJ, Mickey B, Kafrouni AI . Molecular advances to treat cancer of the brain Exp Opin Invest Drugs 2000 9: 1207–1215

    Article  CAS  Google Scholar 

  3. Fathallah-Shaykh HM, Gao W, Cho M, Herrera MA . Priming in the brain, an immunologically-privileged organ, elicits anti-tumor immunity Int J Cancer 1998 75: 266–276

    Article  CAS  Google Scholar 

  4. Fathallah-Shaykh HM et al. Gene transfer of IFN-γ into established brain tumors represses growth by antiangiogenesis J Immunol 2000 164: 217–222

    Article  CAS  Google Scholar 

  5. Fathallah-Shaykh HM et al. Gene transfer into brain parenchyma elicits antitumor effects Cancer Res 2000 60: 1797–1799

    CAS  PubMed  Google Scholar 

  6. Byrnes AP, Rusby JE, Wood MJA, Charlton HM . Adenovirus gene transfer causes inflammation in the brain Neuroscience 1995 66: 1015–1024

    Article  CAS  Google Scholar 

  7. Yang Y, Su Q, Wilson JM . Role of viral antigens in destructive cellular immune responses to adenovirus vector-transduced cells in mouse lungs J Virol 1996 70: 7209–7212

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Dewey RA et al. Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy; implications for clinical research Nature Med 1999 5: 1256–1263

    Article  CAS  Google Scholar 

  9. Marshall E . FDA halts all gene therapy trials at Penn Science 2000 287: 565–566

    Article  CAS  Google Scholar 

  10. Marshall E . Gene therapy on trial Science 2000 288: 951–957

    Article  CAS  Google Scholar 

  11. Ogawa S, Lubahn DB, Korach KS, Pfaff DW . Behavioral effects of estrogen receptor gene disruption in male mice Proc Natl Acad Sci USA 1997 94: 1476–1481

    Article  CAS  Google Scholar 

  12. Stafstrom CE et al. Age dependent cognitive and behavioral deficits after kainic acid seizures Epilepsia 1993 34: 420–432

    Article  CAS  Google Scholar 

  13. Dunn AJ, Swiergiel AH . Behavioral responses to stress are intact in CRF-deficient mice Brain Res 1999 845: 14–20

    Article  CAS  Google Scholar 

  14. Chaouloff F, Kulikov A, Mormede P . Repeated DOI and SR 46349B treatments do not affect elevated plus-maze despite opposite effects on cortical 5-HT2a receptors Eur J Pharmacol 1997 334: 25–29

    Article  CAS  Google Scholar 

  15. Hsiao K et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice Science 1996 274: 99–102

    Article  CAS  Google Scholar 

  16. Morris, R . Development of a water-maze procedure for studying spatial learning in the rat J Neurosci Res 1984 11: 47–60

    CAS  Google Scholar 

  17. Ho CS, Grange RW, Joho RH . Pleiotropic effects of a disrupted K+ channel gene: reduced body weight, impaired motor skill and muscle contraction, but no seizures Proc Natl Acad Sci USA 1997 94: 1533–1538

    Article  CAS  Google Scholar 

  18. Rogan MT, Staubli UV, LeDoux JE . Fear conditioning induces associative long-term potentiation in the amygdala Nature 1997 390: 604–607

    Article  CAS  Google Scholar 

  19. Mayford M et al. Control of memory formation through regulated expression of a CaMKII transgene Science 1996 274: 1678–1683

    Article  CAS  Google Scholar 

  20. Bach ME et al. Impairment of spatial but not contextual memory in CaMKII mutant mice with selective loss of hippocampal LTP in the range of the θ frequency Cell 1995 81: 905–915

    Article  CAS  Google Scholar 

  21. Garcia JA et al. Impaired cued and contextual memory in NPAS2-deficient mice Science 2000 288: 2226–2230

    Article  CAS  Google Scholar 

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This work was supported by grants from the National Cancer Institute (R01-CA81367 and R29-CA78825 to HM Fathallah-Shaykh). Statistical analysis was supported by the Simmons Cancer Center at the University of Texas Southwestern Medical Center at Dallas. We are grateful to Roger Rosenberg for discussions and encouragement. We would also like to acknowledge the support of Mr Theodore Strauss and the Annette Strauss Center for Neuro-Oncology at UT Southwestern Medical Center.

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Fathallah-Shaykh, H., Kafrouni, A., Zhao, LJ. et al. Demyelination but no cognitive, motor or behavioral deficits after adenovirus-mediated gene transfer into the brain. Gene Ther 7, 2094–2098 (2000).

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  • brain
  • gene therapy
  • adenovirus
  • interferon gamma
  • behavior

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