ADENOVIRUS-MEDIATED GENE-TRANSFER TO THE BRAIN - METHODOLOGICAL ASSESSMENT

The purpose of this short review is to analyse major advantages and li mitations of the adenovirus (Ad), specifically with relevance to its u se as a vector for gene transfer to the brain; The characteristics of Ad transduction include: the relative absence of cell type specificity ; the limited spatial spread of the virus; and the long-term expressio n of the transgene. In the central nervous system, in contrast to that which occurs in other organs, Ad transduction in the adult does not s ystematically provoke cell death. Nevertheless, a proportion of the tr ansduced cells do die, and this represents a conspicuous problem. Mech anisms leading to cell death in the brain may include immune rejection and inflammation-related toxicity, although this would not explain al l of the results, and direct toxicity related to either inappropriate preparation or the transduction itself. Taking into account uncertaint ies concerning the innocuousness of Ad transduction, it may seem unwis e to envisage Ad gene therapy for diseases that are not life-threateni ng and/or benefit from adequate drug or surgical treatments (e.g. Park inson's disease or epilepsy). Ad vectors may not be easily used either in diseases displaying major immune dysfunction (e.g. multiple sclero sis). In contrast, malignant brain tumors and numerous neurodegenerati ve diseases (such as Huntington's, Alzheimer's diseases or amyotrophic lateral sclerosis) are directly life-threatening and deprived of any adequate treatment They may be appropriate targets for Ad-mediated gen e therapy, once both the vector and the gene of interest have been def ined and optimized.