Downregulation of the p75 neurotrophin receptor in tissue culture and in vivo, using beta-cyclodextrin-adamantane-oligonucleotide conjugates

Formation of complexes with beta -cyclodextrin derivatives via adamantyl gr oups was found to enhance the uptake and antisense efficacy of phosphorothi oate oligos targeted to the p75 neurotrophin receptor in neuronally differe ntiated PC12 cells, After a 2-week course of systemic administration to mic e (by intraperitoneal injection), there was evidence of a pronounced uptake of these oligos by the dorsal root ganglia (DRG), as well as by liver and kidney. There was no uptake by the brain. Consistent with uptake of antisen se oligos by the DRG, systemic administration resulted in marked and consis tent downregulation of p75 in DRG neurons. These results indicate that cycl odextrin-adamantane-oligo conjugates have great potential as agents to down regulate target genes in neurons, particularly in vivo in the peripheral ne rvous system.