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C. Isiegas, M. Marchena, E. Ayuso, V. Gómez-Vicente, R. Blanco, F. de Pablo, F. Bosch, P. de La Villa, E. de La Rosa; Direct Intravitreal Administration and Systemic AAV-Mediated Delivery of Proinsulin Prevents Retinal Degeneration in the Rd10 Mouse Model of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2009;50(13):697.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies that lead to blindness and for which there is no effective therapy. Apoptosis is a feature common to all cases of RP both in humans and in animal models. We have previously demonstrated that transgenic constitutive expression of the antiapoptotic molecule proinsulin delays retinal degeneration in the rd10 mouse model of RP. The objective of this study is to develop a medically plausible delivery method for proinsulin.
Single intravitreous injections of human proinsulin or vehicle have been performed in rd10 mice at postnatal day 23 (P23) and levels of photoreceptor death have been determined by TUNEL 24 h later. An adeno-associated viral 2/1 (AAV2/1) pseudotyped vector expressing human proinsulin (hPi) under the control of the cytomegalovirus (CMV) promoter has been generated. At P10, rd10 mice received a single intramuscular injection of AAV2/1-hPi or AAV2/1-null (no hPi) vector. In these mice, levels of hPi in serum and in retinal extracts have been measured by ELISA, and visual function has been evaluated by ERG at P30, P40, P50 and P60.
Intravitreous administration of proinsulin attenuated photoreceptor cell death. Proinsulin expression was detected in serum and in retinal extracts from rd10 mice injected AAV2/1-hPi vector into the muscle as measured by ELISA. At P30, rd10 mice injected with AAV2/1-hPi vector displaying serum proinsulin levels across three orders of magnitude demonstrated better vision than controls. Electroretinogram recording along time revealed preservation of retinal function that persisted up to P60 in rd10 mice injected with AAV2/1-hPi vector
Our data show that direct intravitreous supply of proinsulin is effective in preventing photoreceptor cell death in the rd10 mouse. Importantly, our observations showing visual function preservation in the rd10 mice injected with AAV2/1-hPi constitute proof of concept of what we have previously found in the hPi/rd10 transgenic mice, and open the possibility of using AAV vectors with tropism for photoreceptors or retinal pigmented epithelium to locally deliver proinsulin. All together, these data lay solid grounds to develop a proinsulin based therapy for retinitis pigmentosa.
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