Transduction of the Brain

Stable, long-term transgene expression, in the absence of tox-icity, is critical for the use of gene therapy to treat central nervous system (CNS) structural and functional deficits, such as aging-related memory loss, Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis. Zou et al. (85) compared the efficiency, toxicity, and persistence of HDAd and FGAd vector-mediated gene transfer into the CNS of 20-month-old rats. An FG Ad vector or an HDAd-expressing p-galactosidase (5 X 108 particles) was stereotactically injected into the hippocampus or lateral ventricle. Transgene expression peaked 6 days postinjection for both vectors. In the hippocampus, transgene expression from the FGAd decreased rapidly after day 6, being significantly lower than HDAd-injected hippocampus by day 16, and undetectable by day 183. In the ventricle, transgene expression from FGAd was significantly lower than HDAd by day 33 and undetectable by day 66. In contrast, transgene expression from the HDAd remained relatively stable with expression remaining >60% of peak levels on day 183. Overall, expression from HDAd was significantly higher than from FGAd at all time points after 6 days. FGAd induced a substantial inflammatory and immune response as indicated by the presence, proliferation, and activation of microglia and asytocytes, as well as lymphocyte infiltration, which were significantly higher than those induced by HDAd at all time points after 3 h. Although both vectors induced a rapid increase in the proinflammatory cytokine IL-1p that peaked at 3 h postinjection, by 3 days, the level of IL-1p was significantly lower in the HDAd-treated brains than in the FGAd-treated brains. Similarly, both vectors induced the proinflammatory cytokine tumor necrosis factor (TNF)-a reaching peak levels by 3 to 6 h. However, the level of TNF-a remained significantly lower following injection of HDAd compared with FGAd. These results, along with those of Reddy et al. (41) (see Section VI.A) suggest that, although HDAd are significantly less toxic than FG and multiply deleted Ads, they are not completely benign.

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