Barriers and carriers for non-viral delivery of mRNA to induce transient protein expression in the retina: the hurdles of the inner limiting membrane and innate immunity versus the potential of mRNA self-amplification.
Vision loss has a huge impact on patients and their environment. The causes of vision loss often lie in abnormalities in the genetic material of cells in the retina. Messenger RNA (mRNA) administration to the retina has the potential to correct these genetic abnormalities and thus reduce or even reverse the loss of vision. To deliver the mRNA, it is packaged in a nanoparticle that helps the mRNA to reach its target cells. The most safe method to deliver therapeutics to the back of the eye is the injection into the vitreous humor of the eye. Then, nanoparticles have to migrate in the vitreous and cross the inner limiting membrane to reach the retinal cells. To make this process as efficient as possible, we have the first goal to make the nanoparticles as small as possible (<80 nm). Secondly, once it has reached the cells, the mRNA must be efficiently translated to the corresponding protein. However, the cell has defense mechanisms (innate immunity) that detect and destroy the mRNA, so that it is active for only a limited time. We want to extend the residence time of mRNA in the cell by 1. evaluating a mRNA molecule that is capable of replicating itself in the cell (self-amplifying mRNA) and 2. combining mRNA administration with inhibitors of the innate immunity so that mRNA is less recognized and degraded in the cells. Finally, we want to compare the applicability of 'normal' mRNA with 'self-amplifying' mRNA to perform genetic corrections in retinal cells.
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