Conclusion

AS-ODNs are potential neuropharmaceuticals for the treatment of CNS diseases in which overproduction or underproduction of endogenous protein causes pathology. However, because unmodified AS-ODNs are large, highly polar molecules, their passage across the BBB may be limited unless an endogenous transporter is available to promote passage across the BBB. To reach therapeutic concentrations in the CNS, peripherally administered AS-ODNs must be able to cross the BBB in quantities sufficient to affect brain function. Currently, it has been shown that an unmodified phosphorothioate antisense molecule directed at Aß is able to cross the BBB via an active transport mechanism, termed OTS-1 (1). Other unmodified AS-ODNs have been shown to cross the BBB: a P-ODN directed at Met-Enk (unpublished results) and a PNA directed at NTR-1 (2). Future studies of the transport mechanisms that allow antisense molecules to cross the BBB will aid in the elucidation of CNS pathophysiology and also provide a better understanding of the dynamics of the BBB.

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