Stability, clearance, and disposition of intraventricularly administered oligodeoxynucleotides: implications for therapeutic application within the central nervous system.

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