Lipid Nanoparticles Deliver mRNA to Photoreceptors

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Gene therapy for inherited retinal degeneration took another step forward when Oregon researchers used lipid nanoparticles (LNPs) to deliver messenger RNA (mRNA) to the photo­receptors, retinal pigment epithelium (RPE), and Müller glia in mice and nonhuman primates.¹

“We have developed LNPs conju­gated with peptide ligands that reach the back of the eye and bind to pho­toreceptors. These LNPs enabled us to deliver mRNA to the neural retina and [they] could be useful in the develop­ment of mRNA-based gene therapies for inherited blindness,” said Gaurav Sahay, PhD, at Oregon State University and Casey Eye Institute in Portland, Oregon.

Dr. Sahay added, “This is just the beginning. Although there are potential treatments for retinal degeneration, delivering drugs to the right cell type in the eye remains a challenge. We hope this technology will translate into new therapies for inherited diseases through targeted delivery of drugs or genetic material to the cells of interest.”

PROMISE OF NANOTECHNOLOGY. The eventual goal: confirming the ability of lipid nanoparticles to treat inherited blindness in humans (blue = photoreceptors, green and red = retinal bipolar cells, purple = retinal ganglion cells).

Identifying peptide ligands. LNPs, which are tiny, lab-made balls of fat, are excellent carriers for drugs and genetic material. In the team’s previous efforts to develop LNP-based gene therapies for inherited blindness, the LNPs were able to deliver RNA only in the epithelial cells of the eye. For this study, the researchers used a peptide screening assay known as phage display to devel­op LNPs that recognize photoreceptors. “This approach allowed us to identify peptide ligands that target photorecep­tors,” Dr. Sahay noted. The most prom­ising peptides were identified using in vivo biopanning, an “in vivo version of phage display,” he said.

Delivering mRNA to photorecep­tors. Peptides injected intravitreally or subretinally into mice showed rapid localization to the photoreceptors at the back of the eye. Moreover, LNPs coated with peptide ligands crossed biological barriers of the eye and successfully de­livered mRNA to the animals’ photore­ceptors, Müller glia, and RPE.

Commenting on the translational potential of this approach, Dr. Sahay noted that, “with lipid nanoparticles, the rate of translation from nonhuman primate to humans is extremely high.” Moreover, he said, “having positive nonhuman primate data is the next best thing before a human clinical trial.”

Next steps. “Our priority now is to show in multiple animal models that we can treat blindness using peptide-coated LNPs. We also want to study the tolerability of LNPs and perform dose escalation studies in nonhuman primates,” said Dr. Sahay.

Following these proof-of-concept studies, the team is planning to perform clinical trials to confirm the ability of LNPs to act as a gene editing tool. If successful, this would allow researchers to sidestep the limitations associated with current AAV (adeno-associat­ed virus) gene editing strategies, the researchers wrote.

“There are more than 200 mutations in the photoreceptors that cause retinitis. LNPs are very versatile, and if we show that this technology works for one mutation, we will adapt it to target other blindness-causing mutations,” Dr. Sahay added.

—Christos Evangelou, PhD

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1 Herrera-Barrera M et al. Sci Adv. 2023;9(2):eadd4623.

Relevant financial disclosures: Dr. Sahay—Enterx Bio: EO.

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