Peptide-guided lipid nanoparticles deliver mRNA to the neural retina of rodents and nonhuman primates

Marco Herrera-Barrera; Renee C. Ryals; Milan Gautam; Antony Jozic; Madeleine Landry; Tetiana Korzun; Mohit Gupta; Chris Acosta; Jonathan Stoddard; Rene Reynaga; Wayne Tschetter; Nick Jacomino; Oleh Taratula; Conroy Sun; Andreas K. Lauer; Martha Neuringer; Gaurav Sahay

doi:10.1126/sciadv.add4623

Peptide-guided lipid nanoparticles deliver mRNA to the neural retina of rodents and nonhuman primates

Marco Herrera-Barrera, Renee C. Ryals, Milan Gautam, Antony Jozic, Madeleine Landry, Tetiana Korzun, Mohit Gupta, Chris Acosta, Jonathan Stoddard, Rene Reynaga, Wayne Tschetter, Nick Jacomino, Oleh Taratula, Conroy Sun, Andreas K. Lauer, Martha Neuringer, Gaurav Sahay

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Abstract

Lipid nanoparticle (LNP)–based mRNA delivery holds promise for the treatment of inherited retinal degenerations. Currently, LNP-mediated mRNA delivery is restricted to the retinal pigment epithelium (RPE) and Müller glia. LNPs must overcome ocular barriers to transfect neuronal cells critical for visual phototransduction, the photoreceptors (PRs). We used a combinatorial M13 bacteriophage–based heptameric peptide phage display library for the mining of peptide ligands that target PRs. We identified the most promising peptide candidates resulting from in vivo biopanning. Dye-conjugated peptides showed rapid localization to the PRs. LNPs decorated with the top-performing peptide ligands delivered mRNA to the PRs, RPE, and Müller glia in mice. This distribution translated to the nonhuman primate eye, wherein robust protein expression was observed in the PRs, Müller glia, and RPE. Overall, we have developed peptide-conjugated LNPs that can enable mRNA delivery to the neural retina, expanding the utility of LNP-mRNA therapies for inherited blindness.

Original language	English (US)
Article number	eadd4623
Journal	Science Advances
Volume	9
Issue number	2
DOIs	https://doi.org/10.1126/sciadv.add4623
State	Published - Jan 2023

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Herrera-Barrera, M., Ryals, R. C., Gautam, M., Jozic, A., Landry, M., Korzun, T., Gupta, M., Acosta, C., Stoddard, J., Reynaga, R., Tschetter, W., Jacomino, N., Taratula, O., Sun, C., Lauer, A. K., Neuringer, M., & Sahay, G. (2023). Peptide-guided lipid nanoparticles deliver mRNA to the neural retina of rodents and nonhuman primates. Science Advances, 9(2), Article eadd4623. https://doi.org/10.1126/sciadv.add4623

Herrera-Barrera, M, Ryals, RC, Gautam, M, Jozic, A, Landry, M, Korzun, T, Gupta, M, Acosta, C, Stoddard, J, Reynaga, R, Tschetter, W, Jacomino, N, Taratula, O, Sun, C, Lauer, AK , Neuringer, M & Sahay, G 2023, 'Peptide-guided lipid nanoparticles deliver mRNA to the neural retina of rodents and nonhuman primates', Science Advances, vol. 9, no. 2, eadd4623. https://doi.org/10.1126/sciadv.add4623

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title = "Peptide-guided lipid nanoparticles deliver mRNA to the neural retina of rodents and nonhuman primates",

abstract = "Lipid nanoparticle (LNP)–based mRNA delivery holds promise for the treatment of inherited retinal degenerations. Currently, LNP-mediated mRNA delivery is restricted to the retinal pigment epithelium (RPE) and M{\"u}ller glia. LNPs must overcome ocular barriers to transfect neuronal cells critical for visual phototransduction, the photoreceptors (PRs). We used a combinatorial M13 bacteriophage–based heptameric peptide phage display library for the mining of peptide ligands that target PRs. We identified the most promising peptide candidates resulting from in vivo biopanning. Dye-conjugated peptides showed rapid localization to the PRs. LNPs decorated with the top-performing peptide ligands delivered mRNA to the PRs, RPE, and M{\"u}ller glia in mice. This distribution translated to the nonhuman primate eye, wherein robust protein expression was observed in the PRs, M{\"u}ller glia, and RPE. Overall, we have developed peptide-conjugated LNPs that can enable mRNA delivery to the neural retina, expanding the utility of LNP-mRNA therapies for inherited blindness.",

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AU - Gupta, Mohit

AU - Acosta, Chris

AU - Stoddard, Jonathan

AU - Reynaga, Rene

AU - Tschetter, Wayne

AU - Jacomino, Nick

AU - Taratula, Oleh

AU - Sun, Conroy

AU - Lauer, Andreas K.

AU - Neuringer, Martha

AU - Sahay, Gaurav

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Peptide-guided lipid nanoparticles deliver mRNA to the neural retina of rodents and nonhuman primates

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