Emerging biological therapies for age-related macula degeneration.

Age-related macular degeneration (AMD) has emerged as the dominant cause of irretrievable visual loss in most developed countries achieving increasing longevity. The major cause of rapid and severe visual loss is the development of choroidal neovascularisation under the macula (exudative or wet AMD). Physical treatments, especially thermal laser and photodynamic therapy following intravenous verteporfin, have made statistically significant but modest progress in limiting visual loss, whereas surgical translocation of the macula and even light or electrically sensitive retinal implants are spectacular, but likely to only ever benefit a few. Intravitreal fine needle injections and slow release implants of steroid derivatives have opened new areas for investigation. The blocking of endothelial receptors for vascular endothelial growth factor by RNA-based aptamer or immune-protected antibody fragments has been the subject of intensive scientific development and large scale clinical trials. This approach may expand the range of AMD patients amenable to treatment. Additional therapeutic gains await measures to modify photoreceptor cell loss and subretinal fibrosis involving the retinal pigment epithelium as well as prevention or treatment for pigment epithelial detachment. Epidemiological associations with smoking and diet, and antioxidant dietary supplements offer important strategies for prevention.

Preclinical evaluation of a phosphorothioate oligonucleotide in the retina of rhesus monkey.

Overexpression of vascular endothelial growth factor (VEGF) has been strongly implicated in the development of choroidal neovascularization (CNV) in patients with age-related macular degeneration. In this study, a phosphorothioate oligonucleotide (PS-oligo) targeting both human and rat VEGF(165) genes upstream of the translation initiation code, named DS135 in this study, was evaluated for its uptake dynamics and retinal tolerance after intravitreal (IV) and subretinal (SR) injections in the rhesus monkey. Intravitreal and SR injections of a fluorescent-labeled DS135 (FL-DS135) resulted in both dose- and time-dependent uptake and persistence, and FL-DS135 remained detectable in the retina for at least 3 weeks after injection. Ophthalmic examination showed transient vitreous haze after IV delivery of a high dose but not with a low dose of FL-DS135. Histologic examination showed no evidence of retinal degeneration with respect to IV delivery. After SR delivery, however, dose-related cellular infiltration, transient residual fluid, and slight distortion of the neuroretina were observed. The biologic efficacy of DS135 was further assessed in a laser-induced CNV model, and development of CNV was determined by fluorescein angiography and histologic examination. Incomplete inhibition of CNV formation was observed after IV and SR injection of DS135, but no statistically significant difference was achieved when compared with dose-matched control of PS-oligo. Analysis of fluorescein angiogram and histologic examination showed less than 30% incidence of CNV development in this monkey model. Our study demonstrated that PS-oligos can be successfully introduced into the retina, although with potential limitations, after SR delivery. DS135, a PS-oligo targeting the VEGF gene upstream of the translation initiation code, partially inhibited CNV formation. An improved CNV model is necessary for further confirmation of the full therapeutic potency of DS135 before clinical application.