ANTISENSE DRUG-DELIVERY THROUGH THE BLOOD-BRAIN-BARRIER

The blood-brain barrier evolved to protect the brain against periphera l neurotransmitters, cytotoxins and microorganisms. This barrier preve nts the delivery to brain of antisense oligomers and other potential t herapeutics for the treatment of viral infections, tumors, and other b rain disorders. The brain represents a shelter for the human immunodef iciency virus (HIV), for low grade gliomas, and early stages of metast atic tumors to the brain. Non-invasive delivery systems for antisense oligodeoxynucleotide (ODN) therapeutics have been developed that inclu de transcellular avidin-based delivery systems, such as conjugates of avidin analogues and the monoclonal antibody directed to the transferr in receptor (OX26), which targets all tissues expressing these recepto rs including the blood-brain barrier and liver. Although 3'-biotinylat ion of phosphodies ter oligodeoxynucleotides provides complete protect ion against serum and cellular exonuclease-mediated degradation, the i n vivo administration of unconjugated or vector-conjugated biotinylate d PO-ODN results in a rapid degradation through an endonuclease-mediat ed mechanism, thus limiting the efficacy of this potential therapeutic for the brain. This rapid in vivo degradation also occurs with phosph orothioate-ODN containing a single internal phosphodiester bond. Alter natively, a biotinylated peptide nucleic acid (PNA) conjugated to the OX,26-streptavidin delivery system is metabolically stable in vivo and is transported to brain through the blood-brain barrier at a rate 28- fold higher than the oligomer alone. This results in a brain uptake co mparable to that of morphine, a molecule well known for its pharmacolo gical brain effects. In summary, this review discusses different appro aches for delivery of antisense oligonucleotides to the brain and sugg ests that biotinylated PNA conjugated to avidin-based transcellular de livery system represents a model for the delivery of antisense therape utics through the blood-brain barrier.