Recent advances in adenovirus-mediated gene therapy for cerebral ischemia.

Cerebral ischemia induces many degenerative cellular reactions, including the release of excitatory amino acids, the formation of oxygen free radicals, Ca2+ overload, the activation of several cellular enzyme systems such as Ca2+ dependent proteases, and the initiation or genomic responses that can affect the tissue outside the area of reduced blood flow. Furthermore, increasing evidence indicates that apoptosis contributes to the death of brain cells following cerebral ischemia. Several studies have shown that cerebral ischemia alters the expression of genes, some of which may play protective or harmful roles. Although many genes have the potential to treat cerebral ischemia, target genes or their translated products are often difficult to express, if at all, in brain cells. However, adenovirus-mediated gene transfer can overcome this disadvantage. To date, many treatment strategies have been developed for cerebral ischemia using target genes such as neuronal apoptosis inhibitory protein (NAIP), glial cell line-derived neurotrophic factor (GDNF), sensitive to apoptosis gene (SAG), 150-kDa oxygen-regulated protein (ORP150), etc. Moreover, new vectors and gene delivery systems are constantly being invented although there is no perfect vector to date. Gene therapy could constitute a powerful strategy to treat cerebral ischemia in the near future.