Nanotechnology that enabled mRNA-based COVID-19 vaccines could be used to improve gene therapies for inherited retinal diseases (IRDs).
Researchers from Oregon Health & Science University and Oregon State University have collaborated to develop an approach that uses lipid nanoparticles — tiny, lab-made balls of fat — to deliver strands of messenger ribonucleic acid, or mRNA, inside the eye.
To treat IRDs, the mRNA will be designed to create proteins that edit vision-harming gene mutations.
In a study published in Science Advances,1 the team demonstrated that its lipid nanoparticle delivery system targets light-sensitive cells in the eye, called photoreceptors, in both mice and nonhuman primates. The system’s nanoparticles are coated with a peptide that the researchers identified as being attracted to photoreceptors.
“Our peptide is like a zip code, and the lipid nanoparticles are similar to an envelope that sends gene therapy in the mail,” the study’s corresponding author Associate Professor Gaurav Sahay said.2
“The peptide ensures mRNA is precisely delivered to photoreceptors — cells that we haven’t been able to target with lipid nanoparticles until now.”
MORE TREATMENT OPTIONS
Study co-author Dr Renee Ryals said while more than 250 genetic mutations have been linked to IRDs, only one has an approved gene therapy.
“Improving the technologies used for gene therapy can provide more treatment options to prevent blindness. Our study’s findings show that lipid nanoparticles could help us do just that.”
Today’s gene therapies largely rely on a modified version of the adeno-associated virus, or AAV, to deliver gene-revising molecules. But this has some limitations. The virus is relatively small and can’t physically contain gene-editing machinery for some complex mutations. Additionally, AAV-based gene therapy can only deliver DNA, which results in the continual creation of gene-editing molecules that may lead to unintended genetic edits.
Lipid nanoparticles are a promising alternative because they don’t have size constraints like AAV. Additionally, lipid nanoparticles can deliver mRNA, which only keeps gene-editing machinery active for a short period of time, so could prevent off-target edits.
The research built on coronavirus vaccines, which used mRNA carried by the liquid nanoparticles to instruct cells to make a harmless piece of the virus’ spike protein, triggering an immune response from the body.
In this study, as a first proof of concept, mRNA with instructions to make green fluorescent protein was placed inside nanoparticles, then injected into the eyes of mice and nonhuman primates.
The research team used a variety of imaging techniques to examine the treated eyes. The animals’ retinal tissue glowed green, illustrating that the lipid nanoparticle shell reached photoreceptors and that the mRNA it delivered successfully entered the retina and created green fluorescent protein.
This research marks the first time that lipid nanoparticles are known to have targeted photoreceptors in a nonhuman primate.
1. Herrera-Barrera, M., Ryals, R.C., Gautam M., et al., “Peptideguided lipid nanoparticles deliver mRNA to the neural retina ofrodents and nonhuman primates,” Science Advances, Jan. 11, 2023, DOI: 10.1126/sciadv.add4623