Phosphorothioate oligonucleotides induction into experimental choroidal neovascularization by HVJ-liposome system

Abstract

Phosphorothioate oligonucleotides can be effectively induced into ganglion cells, and specifically into cells in choroidal neovascularization. Although antisense oligonucleotides against VEGF failed to prevent choroidal neovascularization, the HVJ-liposome method provided a highly effective means of inducing antisense oligos for in vivo antisense therapy.

Preclinical Evaluation of a Phosphorothioate Oligonucleotide in the Retina of Rhesus Monkey

“…There have been several investigations in the use of antisense PSoligos targeting VEGF to inhibit retinal and choroidal neovascularization (Ogata et al, 1999;Robinson et al, 1996). However, data from all previous investigations demonstrated either incomplete or ineffective inhibition (Ogata et al, 1999;Robinson et al, 1996). Incomplete inhibition of CNV by DS135 might indicate that other angiogenic factors are involved in the process of CNV, implying the complexity regarding the pathogenesis of CNV (Mousa et al, 1999;Takahashi et al, 2000).…”

“…There have been several investigations in the use of antisense PSoligos targeting VEGF to inhibit retinal and choroidal neovascularization (Ogata et al, 1999;Robinson et al, 1996). However, data from all previous investigations demonstrated either incomplete or ineffective inhibition (Ogata et al, 1999;Robinson et al, 1996).…”

“…Previous investigations have demonstrated a preferential distribution of PS-oligo at laser lesions (Ogata et al, 1999;Shen et al, 1999). The accumulation of PS-oligos at laser lesions might be associated with altered cell membranes with a higher affinity for fusion but most likely reflects the activity of the cells during the development of CNV (Zhang et al, 1993).…”

“…However, indirect ophthalmoscopy revealed transient vitreous haze with a high dosage (50 l, 7.5 nmol/ l) of DS135, indicating a possibly transient inflammatory response in the vitreous cavity. To date, most studies have involved IV administration of PS-oligo into the eye (Dvorchik and Marquis, 2000;Flores-Aguilar et al, 1997;Hangai et al, 1998;Leeds et al, 1997Leeds et al, , 1998Ogata et al, 1999;Rakoczy et al, 1996;Robinson et al, 1996;Shen et al, 1999;Stone and Jaffe, 2000). It has been reported that high doses of PS-oligos after IV injection induce cataract, severe inflammatory response, increased intraocular pressure, maculopathy, and permanent retinal damage (Detrick, 2001;Dvorchik and Marquis, 2000;Flores-Aguilar et al, 1997;Stone and Jaffe, 2000).…”

In vivo gene transfer into choroidal neovascularization by the HVJ liposome method

“…Choroidal neovascularization was detected by fluorescein angiography following photocoagulation in control eyes without the injection of HVJ liposome solution as previously reported [42][43][44]56] (data not shown). Most of the eyes injected with HVJ liposomes were cloudy from the HVJ liposome suspension and thus could not be examined by fluorescein angiography.…”