Topical Ocular Delivery of TGF-ß1 to the Back of the Eye: Implications in Age-Related Neurodegenerative Diseases.

Dysregulation of the transforming growth factor-ß1 (TGF-ß1)/selected small mother against decapentaplegic (SMAD) pathway can be implicated in development of age-related macular degeneration (AMD), and the delivery of TGF-ß1 could be beneficial for AMD. We developed a new ophthalmic formulation of TGF-ß1 assessing the ocular pharmacokinetic profile of TGF-ß1 in the rabbit eye. Small unilamellar vesicles (SUV) loaded with TGF-ß1 were complemented with Annexin V and Ca2+, and the vitreous bioavailability of TGF-ß1 was assessed after topical ocular administration by a commercial ELISA kit. We detected high levels of TGF-ß1 (Cmax 114.7 ± 12.40 pg/mL) in the vitreous after 60 min (Tmax) from the topical application of the liposomal suspension. Ocular tolerability was also assessed by a modified Draize's test. The new formulation was well tolerated. In conclusion, we demonstrated that the novel formulation was able to deliver remarkable levels of TGF-ß1 into the back of the eye after topical administration. Indeed, this TGF-ß1 delivery system may be useful in clinical practice to manage ophthalmic conditions such as age-related macular degeneration, skipping invasive intraocular injections.

TGF-ß1 prevents rat retinal insult induced by amyloid-ß (1-42) oligomers.

To set up a retinal degenerative model in rat that mimics pathologic conditions such as age-related macular degeneration (AMD) using amyloid-ß (Aß) oligomers, and assess the effect of TGF-ß1. Sprague-Dawley male rats were used. Human Aß1-42 oligomers were intravitreally (ITV) injected (10µM) in the presence or in the absence of recombinant human TGF-ß1 (1ng/µl ITV injected). After 48h, the animals were sacrificed and the eyes removed and dissected. The apoptotic markers Bax and Bcl-2 were assessed by western blot analysis in retina lysates. Gene-pathway network analysis was carried out in order to identify pathways involved in AMD. Treatment with Aß oligomers induced a strong increase in Bax protein level (about 4-fold; p<0.01) and a significant reduction in Bcl-2 protein level (about 2-fold; p<0.05). Co-injection of TGF-ß1 triggered a significant reduction of Bax protein induced by Aß oligomers. Bioinformatic analysis revealed that Bcl-2 and PI3K-Akt are the most connected nodes, for genes and pathways respectively, in the enriched gene-pathway network common to AMD and Alzheimer disease (AD). Overall, these data indicate that ITV injection of Aß1-42 oligomers in rat induces molecular changes associated with apoptosis in rat retina, highlighting a potential pathogenetic role of Aß oligomers in AMD. Bioinformatics analysis confirms that apoptosis pathways can take part in AMD. Furthermore, these findings suggest that human recombinant TGF-ß1 can prevent retinal damage elicited by Aß oligomers.