STABILITY, CLEARANCE, AND DISPOSITION OF INTRAVENTRICULARLY ADMINISTERED OLIGODEOXYNUCLEOTIDES - IMPLICATIONS FOR THERAPEUTIC APPLICATION WITHIN THE CENTRAL-NERVOUS-SYSTEM

We report experiments in the rat demonstrating the feasibility of intr aventricular administration of oligodeoxynucleotides (ODNs) as a regio nal treatment approach to disorders within the central nervous system (CNS). Although we find little intrinsic nuclease activity in cerebros pinal fluid (CSF), phosphodiester ODNs are rapidly degraded by brain-a ssociated alpha-exonuclease activity. Phosphorothioate ODNs, however, appear resistant to degradation in the CNS and, after intraventricular administration, we find they are cleared in a manner consistent with CSF bulk flow. Continuous infusion of ODN at 1.5 nmol/hr by miniosmoti c pump can maintain micromolar concentrations of intact phosphorothioa te ODN in CSF for at least 1 week without obvious neurologic or system ic toxicity. After infusion, extensive brain penetration and marked ce llular uptake, especially by astrocytic cells, is demonstrated.