Antiviral activity and ocular kinetics of antisense oligonucleotides designed to inhibit CMV replication

摘要: PURPOSE. To compare the antiviral activity and ocular distribution of first- second-generation antisense oligonucleotides intended for treatment cytomegalovirus (CMV) retinitis. METHODS. The ISIS 13312 2922 (Isis Pharmaceuticals, Inc., Carlsbad, CA) against 10 clinical CMV isolates was compared with a plaque-reduction assay. pharmacokinetics were after intravitreal injection in rabbits (36 ‐90 mg) monkeys (125‐500 mg). Vitreous and/or retina collected single multiple injections to characterize distribution, clearance, accumulation. Oligonucleotide concentrations measured by capillary gel electrophoresis immunohistochemical techniques. RESULTS. demonstrated comparable that consistent among examined (50% inhibitory concentration [IC50], ,1 mM). Activity independent resistance DNA polymerase inhibitors. After injection, kinetics characterized clearance from vitreous retina; however, cleared more quickly than 13312. half-life monkey approximately 2 months. Retinal dose dependent, twofold increase once-monthly doses single-dose concentrations. Immunohistochemical analysis indicated both efficiently distributed numerous tissues, including retina, ciliary body, optic nerve. CONCLUSIONS. possesses pharmacokinetic properties favor its use as therapeutic agent is longer 2922, potentially allowing less frequent administration. (Invest Ophthalmol Vis Sci. 2001; 42:2646 ‐2651)