A team of researchers from Oregon Health & Science University and Oregon State University (USA) have developed an mRNA-based method similar to that used for Covid-19 vaccines to treat blindness. As explained in a study published in “Science Advances”, the new system uses lipid nanoparticles -small balls of fat made in the laboratory- to deliver chains of messenger ribonucleic acid, or mRNA, inside the eye. That is, the mRNA is designed in order to make proteins that edit genetic mutations that are harmful to vision.
In their study, the team demonstrates how their lipid nanoparticle delivery method targets light-sensitive cells in the eye, called photoreceptors, in both mice and non-human primates. The system’s nanoparticles are coated with a peptide that the researchers say attracts photoreceptors.
“Our peptide is like a zip code, and lipid nanoparticles are similar to an envelope that gene therapy sends in the mail,” explains study author Gaurav Sahay, an associate professor at the OSU College of Pharmacy. “The peptide ensures that the mRNA precisely reaches the photoreceptors, cells that until now we have not been able to target with lipid nanoparticles.”
There are currently more than 250 gene mutations linked to inherited retinal diseases, “but only one has an approved gene therapy,” says study co-author Renee Ryals, an associate professor of ophthalmology at the OHSU College of Medicine. “Improved technologies used for gene therapy may provide more treatment options to prevent blindness. The findings from our study show that lipid nanoparticles could help us do just that.”
In 2017, the first gene therapy to treat an inherited form of blindness. Many patients have experienced improved vision and been rid of blindness after receiving the therapy, which uses a modified version of the adeno-associated virus, or AAV, to deliver gene-modifying molecules.
Current gene therapies are largely based on AAV, but it has some limitations. The virus is relatively small and cannot physically contain gene-editing machinery for some complex mutations. Furthermore, AAV-based gene therapy can only deliver DNA, which causes the continuous creation of gene editing molecules that can lead to unwanted gene edits.
Lipid nanoparticles are a promising alternative because they do not have size limitations like AAV. Furthermore, lipid nanoparticles can release mRNA, which only keeps the gene-editing machinery active for a short period of time, potentially preventing unwanted editing. The potential of lipid nanoparticles was demonstrated by the success of mRNA-based Covid-19 vaccines, which also use lipid nanoparticles to deliver mRNA.
The potential of lipid nanoparticles was demonstrated by the success of mRNA-based Covid-19 vaccines
In this study, Sahay, Ryals, and their colleagues showed that a peptide-coated coat of lipid nanoparticles can target photoreceptor cells in the retina, the tissue at the back of the eye that enables vision. As a first proof of concept, mRNA with instructions for making green fluorescent protein was placed inside nanoparticles.
After injecting this nanoparticle-based gene therapy model into the eyes of mice and non-human primates, the research team used various imaging techniques to examine the treated eyes. The retinal tissue of the animals was illuminated green, demonstrating that the lipid nanoparticle shell reached the photoreceptors and that the released mRNA penetrated the retina and created the green fluorescent protein. It is the first time that lipid nanoparticles are known to target photoreceptors in a non-human primate.