The collaboration between ZeClinics and Dompé Farmaceutici started a few years ago. The challenge that we sought to tackle was to demonstrate that zebrafish can be used to reliably model human retinopathies and, most importantly, to test potential therapeutic approaches.
Retinal conditions are characterized by progressive bilateral degeneration of the rod and cone photoreceptors, ultimately leading to either partial or total visual impairment. Several potential approaches have been developed to delay the progression of these diseases, but currently, no therapy able to promote the reversion of the phenotype is still available.
Indeed, to date, rodents and rabbits are the most commonly used animal model for drug delivery for retinopathy treatments, while the use of zebrafish to test intraocular administration of therapeutic or neuroprotective compounds is scarce. Dompé Farmaceutici is an excellent example of a pharmaceutical company who decided to bet on the advantages of this alternative model to gain more insights on the mechanism of action of its FDA-approved recombinant human NGF (rhNGF).
Notably, increasing lines of evidence have shown that NGF can be crucial for the treatment of blinding diseases, such as retinal degenerations, and several studies have already described the protective effect of NGF administration in experimental models of retinitis pigmentosa (RP) and age-related macular degeneration (AMD).
In our study, we assessed the potential regenerative effect of intravitreal (IV) administration of rhNGF using a retinal degeneration paradigm in adult zebrafish based on constant light irradiation. Unlike mammals that cannot regenerate their retina after damage or degeneration, the zebrafish retina displays a robust regenerative response upon injury, and this feature can be exploited to gain insights into molecular mechanisms underlying healing of damaged tissues in eye human pathology.
Therefore, we propose the zebrafish as a powerful alternative model for testing the efficacy of novel potential IV-injection based treatment of retinal diseases, with the possibility of medium-throughput assessment of toxicity and pharmacokinetics. To date, vascular endothelial growth factor (VEGF) inhibitors are the most widely used compounds for the treatment of intraocular disorders (DOI: 10.1038/nrd.2015.17). Nonetheless, amelioration of patients’ condition is subject to frequent injections throughout several years (DOI: 10.1073/pnas.1921252118), representing a heavy burden on health systems. For this reason, there is a need for more effective and long-lasting treatments that can be implemented in clinical settings. Importantly, we have shown that a single intravitreal injection of rhNGF is able to lead to a mild amelioration of damaged zebrafish retinal tissue in a short time window, likely due to enhanced cell proliferation.
Our results demonstrate the highly conserved nature of NGF canonical pathway in adult zebrafish retina and that administration of rhNGF can boost zebrafish retinal regeneration upon injury.
In light of our data and considerations, our study opens the way to the use of zebrafish as a useful model to test new compounds potentially able to stimulate the regeneration properties of the retina.
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