Assessing viral gene therapy in neuroendocrine models

A simple method of manipulating neuronal gene expression would greatly faci litate the design of experiments to increase our understanding of and abili ty to treat diseases of the CNS. However, until recently most transfection methods could only deliver DNA into dividing cells and it was only possible to manipulate neuronal gene expression through the production of transgeni c animals. The development of powerful new viral-based gene transfer system s has generated a great deal of research interest: in the field of therapeu tic gene transfer during the last decade. One of the most powerful and vers atile gene delivery systems currently available is the recombinant adenovir us (Ad) vector. These vectors can transfect postmitotic neurons in the CNS, but have not yet been fully evaluated as CNS gene therapy vectors. Brattle boro rats contain a point mutation in the arginine vasopressin (AVP) gene t hat results in a pathological phenotype characterized by a lack of circulat ing AVP. This decrease in AVP in turn causes the characteristics signs of d iabetes insipidus, with the production of large volumes of dilute urine and a compensatory drinking of large volumes of water (equivalent to the body weight of the rat per day). We have shown that injection of an Ad encoding the arginine vasopressin cDNA into the supraoptic nuclei of the hypothalamu s results in the long-term reversal of this pathological phenotype. This wa s demonstrated by reduced daily water intake and micturition, as well as in creased urine osmolality lasting 4 months. The highly characterized Brattle boro rat model of hypothalamic diabetes insipidus, therefore, provides the means to examine noninvasively the efficacy of viral and nonviral gene ther apy strategies in the CNS. (C) 1999 Academic Press.