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 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), p...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1993-05, Vol.90 (10), p.4665-4669
Main Authors: Whitesell, Luke, Geselowitz, Daniel, Chavany, Christine, Fahmy, Brigid, Walbridge, Stuart
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Biological and medical sciences
Boluses
Central nervous system
Cerebrospinal fluid
Electrophoresis
Female
Fluorescence
Gels
General pharmacology
Injections, Intraventricular
Material degradation
Materials
Medical sciences
Medical treatment
Microscopy, Fluorescence
Molecular Sequence Data
Oligodeoxyribonucleotides - administration & dosage
Oligodeoxyribonucleotides - chemistry
Oligodeoxyribonucleotides - pharmacokinetics
Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions
Pharmacology. Drug treatments
Pumps
Rats
Rats, Sprague-Dawley
Thionucleotides - chemistry
Tissue Distribution
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Summary: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 α-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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.90.10.4665