Less is more: Self-amplifying mRNA becomes self-killing upon dose escalation in immune-competent retinal cells.

Publication date: Jan 30, 2024

In the last few years, mRNA therapeutics experienced a new wave of interest as therapy for retinal diseases. Nevertheless, despite the widespread use of mRNA vaccines in the COVID-19 pandemic, mRNA delivery to the eye is still in its infancy. Recently, our research group has demonstrated that after subretinal and intravitreal delivery of modified mRNA, the number of transfected retinal cells and protein expression per cell remains limited. In this study, we aimed to tackle this limitation by using self-amplifying mRNA (saRNA), which in theory will increase the duration and level of protein expression when only a few mRNA molecules reach their target cells. A one-on-one comparison between modified mRNA and saRNA in two immune-competent human retinal cell types, including McFCller cells and retinal pigment epithelial cells, and in immune-deficient BHK-21 cells revealed that saRNA delivery induced an innate immune response blocking its own translation above a certain dose threshold. Removal of double-stranded (ds)RNA byproducts by cellulose-based purification and addition of the innate immune inhibitor B18R remarkably improved translation from saRNA through a reduction in innate immune response. Taken together, when saRNA is applied for retinal disease, the dose should be controlled and measures should be taken to limit immunogenicity.

Concepts Keywords
Biopharm Dose titration
Immunogenicity Innate immune stimulation
Killing mRNA
Mrna Retinal gene therapy
Therapy Self-amplifying mRNA


Type Source Name
disease VO dose
disease MESH retinal diseases
disease MESH COVID-19 pandemic
disease IDO cell
disease IDO innate immune response
pathway REACTOME Translation
drug DRUGBANK Microcrystalline cellulose
disease VO gene

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