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  • Title: Hypothalamic delivery of doxycycline-inducible leptin gene allows for reversible transgene expression and physiological responses.
    Author: Wilsey J, Zolotukhin S, Prima V, Shek EW, Matheny MK, Scarpace PJ.
    Journal: Gene Ther; 2002 Nov; 9(22):1492-9. PubMed ID: 12407421.
    Abstract:
    Our purpose was to incorporate regulation into the recombinant adeno-associated virus encoding leptin by introducing a tet-inducible promotor. This system, TET-Ob, allows for control of leptin gene expression via doxycycline in drinking water. F344XBN rats (aged 4 months) were given a hypothalamic injection of TET-Ob or control virus. During 34 days of doxycycline (doxy) administration to all rats (STAGE 1), TET-Ob rats gained 50.7% less mass, ate 10.4% less food, and had a 77.5% reduction in serum leptin as compared with controls. Doxy was then withdrawn from half of the TET-Ob rats for 32 days (TET-Ob-OFF), while half continued to receive doxy (TET-Ob-ON) (stage 2). During stage 2, TET-Ob-ON rats gained 44.8% less mass than TET-Ob-OFF and ate significantly less food than both TET-Ob-OFF and controls. Serum leptin increased to 83.4% of control values in TET-Ob-OFF, but remained very low in the in TET-Ob-ON. At death, visceral adiposity was 14.5% of controls in TET-Ob-ON animals, but had risen to 76.9% of controls in TET-Ob-OFF. A reversible increase in both leptin signal transduction in the hypothalamus and uncoupling protein expression in brown adipose was recorded. This system allows for more precise regulation of gene therapy-mediated fat loss.
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