HIGHLY EFFICIENT AND SUSTAINED GENE-TRANSFER IN ADULT NEURONS WITH A LENTIVIRUS VECTOR

The identification of monogenic and complex genes responsible for neur ological disorders requires new approaches for delivering therapeutic protein genes to significant numbers of cells in the central nervous s ystem. A lentivirus-based vector capable of infecting dividing and qui escent cells aas investigated in vivo by injecting highly concentrated viral vector stock into the striatum and hippocampus of adult rats. C ontrol brains were injected,vith a Moloney murine leukemia virus, aden ovirus, or adeno-associated virus vector. The volumes of the areas con taining transduced cells and the transduced-cell densities were stereo logically determined to provide a basis for comparison among different viral vectors and variants of the viral vector stocks. The efficiency of infection by the lentivirus vector was improved by deoxynucleoside triphosphate pretreatment of the vector and was reduced following mut ation of integrase and the Vpr-matrix protein complex involved in the nuclear translocation of the preintegration complex. The lentivirus ve ctor system was able to efficiently and stably infect quiescent cells in the primary injection site with transgene expression for over 6 mon ths. Triple labeling showed that 88.7% of striatal cells transduced by the lentivirus vector were terminally differentiated neurons.