Evaluation of retinal toxicity and efficacy of anti-cytomegalovirus and anti-herpes simplex virus antiviral phosphorothioate oligonucleotides ISIS 2922 and ISIS 4015.
Retinal toxicity of ISIS 2922 and ISIS 4015, phosphorothioate oligonucleotides complementary to human cytomegalovirus (CMV) and herpes simplex virus (HSV) RNA, were evaluated. The intravitreal concentration of ISIS 2922 found not to cause permanent toxic changes in the rabbit retina was 10 microM and in the pig retina, 5 microM. The 3 microM concentration was associated with a transient inflammatory response, and 1 microM caused no retinal toxicity or inflammation. ISIS 4015 showed very mild toxicity with no permanent retinal changes and very mild inflammation at doses of 10 microM; this dose was effective in ameliorating or preventing HSV-1 retinitis when injected 1 day and 1 week prior to virus inoculation. These oligonucleotides have a low intraocular therapeutic index. Attempts to improve the therapeutic index of these compounds are indicated. Only a clinical trial can determine the toxicity profile of ISIS 2922 for the treatment of CMV retinitis.
Flores-Aguilar
M
M
Shiley Eye Center, University of California, San Diego, La Jolla 92093, USA.
Besen
G
G
Vuong
C
C
Tatebayashi
M
M
Munguia
D
D
Gangan
P
P
Wiley
C A
CA
Freeman
W R
WR
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use* / Q000633:toxicity; D003587:Cytomegalovirus / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use / Q000633:toxicity*; D011817:Rabbits; D012160:Retina / Q000187:drug effects*; D012173:Retinitis / Q000188:drug therapy / Q000517:prevention & control*; D013552:Swine; D013873:Thionucleotides / Q000627:therapeutic use / Q000633:toxicity
D000998:Antiviral Agents; C106318:ISIS 4015; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; C091346:fomivirsen