Ocular enzyme delivery and nanotechnology : expanding the therapeutic horizon for vitreoretinal diseases

Subtitle:Enzym aflevering en nanotechnologie in oculaire context : het verbreden van de therapeutische horizon voor vitreoretinale aandoeningen

In this dissertation, we covered three different topics focusing on ocular drug delivery for the treatment of (vitreo)retinal diseases. First, we provided an in-depth introduction to the structural and biochemical changes that occur in the vitreous humor with aging and disease. This can induce anomalous posterior vitreous detachment, resulting in vision impairment. Pharmacological vitreolysis was proposed as a treatment strategy and although many enzymatic agents have been evaluated, retinal toxicity remained a hurdle. Therefore, we investigated the potential of enzyme immobilization on the surface of nanoparticles to reduce or completely eliminate enzymatic toxicity. We succeeded to reduce retinal toxicity upon injection in ex vivo bovine vitreoretinal explants. These results were confirmed in vivo, as retinal function was nicely preserved upon intravitreal injection of enzyme-modified nanoparticles in rabbits. Despite the need for further optimization, this study has proven the potential of enzyme immobilization and opened doors for future research. In the second part of this dissertation, we measured the intravitreal mobility and stability of FN3K, a deglycating enzyme that has recently proven its potential in the treatment of AMD and cataract. We were able to demonstrate that FN3K remains stable in vitreous as no aggregation or degradation was observed. In the third part of this thesis, we provided an in-depth overview of mRNA and its immunogenicity, which reduces mRNA translation and is therefore considered a drawback in non-immunotherapy applications. We reviewed the contemporary strategies to reduce or eliminate this innate immune stimulation, and evaluate the role of the innate immune inhibitor B18R to increase mRNA translation. Although B18R was able to reduce mRNA immunogenicity and increase mRNA translation in RPE cells, this was not the case for Müller cells. Future studies to investigate Müller cell immune reactivity are of interest.

Publication year:2022

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