Antiangiogenic activity of aganirsen in nonhuman primate and rodent models of retinal neovascular disease after topical administration.

PURPOSE: Aganirsen, an antisense oligonucleotide inhibiting insulin receptor substrate (IRS)-1 expression, has been shown to promote the regression of pathologic corneal neovascularization in patients. In this study, the authors aimed to demonstrate the antiangiogenic activity of aganirsen in animal models of retinal neovascularization. METHODS: Eyedrops of aganirsen were applied daily in nonhuman primates after laser-induced choroidal neovascularization (CNV; model of wet age-related macular degeneration [AMD]) and in newborn rats after oxygen-induced retinopathy (OIR; model of ischemic retinopathy). Retinal aganirsen concentrations were assessed in rabbits and monkeys after topical delivery (21.5, 43, or 86 µg). Clinical significance was further evaluated by determination of IRS-1 expression in monkey and human retinal biopsy specimens. RESULTS: Topical corneal application of aganirsen attenuated neovascular lesion development dose dependently in African green monkeys. The incidence of high-grade CNV lesions (grade IV) decreased from 20.5% in vehicle-treated animals to 1.7% (P < 0.05) at the 86-µg dose. Topical aganirsen inhibited retinal neovascularization after OIR in rats (P < 0.05); furthermore, a single intravitreal injection of aganirsen reduced OIR as effectively as ranibizumab, and their effects were additive. Significantly, topical applications of aganirsen did not interfere with physiological retinal vessel development in newborn rats. Retinal delivery after topical administration was confirmed, and retinal expression of IRS-1 was demonstrated to be elevated in patients with subretinal neovascularization and AMD. CONCLUSIONS: Topical application of aganirsen offers a safe and effective therapy for both choroidal and retinal neovascularization without preventing its normal vascularization. Together, these findings support the clinical testing of aganirsen for human retinal neovascular diseases.

Myelinogenesis in the brachial and lumbosacral enlargements of the spinal cord of the opossum Monodelphis domestica.

Using immunohistochemistry in light microscopy, the myelin basic protein and proteolipid protein were localized on sections of the spinal cord enlargements of opossums, Monodelphis domestica, to determine the timecourse of myelinogenesis therein and compare it with other events of motor systems development. Additional tissue not processed for immunohistochemistry was prepared for transmission electron microscopy. No immunolabeling for either protein occurred on spinal sections from the newborn opossum, but in electron microscopy occasional fibers surrounded by loose, irregular membranous rings were seen on the outskirts of the ventral horn. Immunolabeling was detected first in the brachial enlargement during the second week, presumably on motoneuronal, vestibular and reticular axons. The areas of the dorsal columns, other spino-encephalic, reticulospinal and propriospinal projections became labeled in the third week, and the area of rubrospinal axons at 4 weeks. In the brachial gray matter, immunolabeling appeared along ventrodorsal and lateromedial gradients from the fourth to seventh weeks. Labeling developed similarly in the white and gray matter of the lumbosacral enlargement, but 3-5 days later than at brachial levels. Labeling intensity in the white and gray matter increased until at least 4 months, but remained light in laminae I-III. Thus, myelinogenesis in the spinal cord enlargements of the opossum is protracted and follows general rostrocaudal, ventrodorsal and lateromedial sequences. It occurs later than synaptogenesis at comparable levels of the cord, but earlier than myelinogenesis in the corresponding ventral and dorsal roots. Spinal myelinogenesis correlates with the development of sensorimotor reflexes, weight support and quadrupedal locomotion.