Transport of Antisense Across the Blood-Brain Barrier

Antisense-mediated therapy holds great promise for the treatment of central nervous system (CNS) diseases in which neurodegeneration is linked to over-production of endogenous protein. Administration of antisense therapy could be difficult, however, because peripherally administered antisense would have to cross the blood-brain barrier (BBB) in effective quantities. Several studies have investigated various modifications that can be introduced into antisense molecules to improve their ability to cross the BBB. Recently, two types of unmodified antisense analogs have been shown to effectively cross the BBB and affect CNS function. One of the analogs, a phosphorothioate oligodeoxy-nucleotide (P-ODN) directed against the amyloid β protein, was peripherally administered via iv injection. This analog crosses the BBB via a saturable transport mechanism termed oligonucleotide transport system-1 (OTS-1) (1 ). Another unmodified P-ODN was also shown to cross the BBB. This P-ODN was directed at methionine enkephalin (Met-Enk), an opiate peptide associated with alcoholism (unpublished results). The second type of unmodified analog shown to cross the BBB is a peptide nucleic acid (PNA) that was directed against the neurotensin receptor NTS-1 in rats and was administered via ip injection (2 ). Antisense molecules that can cross the BBB would be potential therapeutic agents and useful tools in the elucidation of CNS pathophysiology.