Stability, clearance, and disposition of intraventricularly administered oligodeoxynucleotides: implications for therapeutic application within the central nervous system.
L Whitesell, D Geselowitz, C Chavany… - Proceedings of the …, 1993 - National Acad Sciences
L Whitesell, D Geselowitz, C Chavany, B Fahmy, S Walbridge, JR Alger, LM Neckers
Proceedings of the National Academy of Sciences, 1993•National Acad SciencesWe report experiments in the rat demonstrating the feasibility of intraventricular
administration of oligodeoxynucleotides (ODNs) as a regional treatment approach to
disorders within the central nervous system (CNS). Although we find little intrinsic nuclease
activity in cerebrospinal fluid (CSF), phosphodiester ODNs are rapidly degraded by brain-
associated alpha-exonuclease activity. Phosphorothioate ODNs, however, appear resistant
to degradation in the CNS and, after intraventricular administration, we find they are cleared …
administration of oligodeoxynucleotides (ODNs) as a regional treatment approach to
disorders within the central nervous system (CNS). Although we find little intrinsic nuclease
activity in cerebrospinal fluid (CSF), phosphodiester ODNs are rapidly degraded by brain-
associated alpha-exonuclease activity. Phosphorothioate ODNs, however, appear resistant
to degradation in the CNS and, after intraventricular administration, we find they are cleared …
We report experiments in the rat demonstrating the feasibility of intraventricular administration of oligodeoxynucleotides (ODNs) as a regional treatment approach to disorders within the central nervous system (CNS). Although we find little intrinsic nuclease activity in cerebrospinal fluid (CSF), phosphodiester ODNs are rapidly degraded by brain-associated 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 miniosmotic pump can maintain micromolar concentrations of intact phosphorothioate ODN in CSF for at least 1 week without obvious neurologic or systemic toxicity. After infusion, extensive brain penetration and marked cellular uptake, especially by astrocytic cells, is demonstrated.
National Acad Sciences