{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T07:56:41Z","timestamp":1775894201113,"version":"3.50.1"},"posted":{"date-parts":[[2025,3,13]]},"group-title":"Biochemistry","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T00:00:00Z","timestamp":1741824000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Small interfering RNAs (siRNAs) are a proven therapeutic approach for controlling gene expression in the liver. Expanding the clinical potential of RNA interference (RNAi) requires developing strategies to enhance delivery to extra-hepatic tissues. In this study we examine inhibiting\n                  <jats:italic>transthyretin<\/jats:italic>\n                  (\n                  <jats:italic>TRR<\/jats:italic>\n                  ) gene expression by short interfering RNAs (siRNAs) in the eye. Anti-\n                  <jats:italic>TTR<\/jats:italic>\n                  siRNAs have been developed as successful drugs to treat TTR amyloidosis. When administered systemically, anti-\n                  <jats:italic>TTR<\/jats:italic>\n                  siRNAs alleviate symptoms by blocking\n                  <jats:italic>TTR<\/jats:italic>\n                  expression in the liver. However, TTR amyloidosis also affects the eye, suggesting a need for reducing ocular\n                  <jats:italic>TTR<\/jats:italic>\n                  gene expression. Here, we demonstrate that C5 and 2\u2019-O-linked lipid-modified siRNAs formulated in saline can inhibit\n                  <jats:italic>TTR<\/jats:italic>\n                  expression in the eye when administered locally by intravitreal (IVT) injection. Modeling suggests that length and accessibility of the lipid chains contributes to\n                  <jats:italic>in vivo<\/jats:italic>\n                  silencing. GalNAc modified anti-dsRNAs also inhibit\n                  <jats:italic>TTR<\/jats:italic>\n                  expression, albeit less potently. These data support lipid modified siRNAs as an approach to treating the ocular consequences of TTR amyloidosis. Inhibition of\n                  <jats:italic>TTR<\/jats:italic>\n                  expression throughout the eye demonstrates that lipid-siRNA conjugates have the potential to be a versatile platform for ocular drug discovery.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"642595v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.11.642595","type":"posted-content","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T01:20:21Z","timestamp":1741915221000},"source":"Crossref","is-referenced-by-count":0,"title":["Modulation of\n                  <i>TTR<\/i>\n                  Gene Expression in the Eye using Modified Duplex RNAs"],"prefix":"10.64898","author":[{"given":"Jiaxin","family":"Hu","sequence":"first","affiliation":[{"name":"UT Southwestern Medical Center, Departments of Pharmacology and Biochemistry, Dallas TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Gong","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center, Department of Ophthalmology, Dallas, TX 75235, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jayanta","family":"Kundu","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals, Cambridge, MA, 04142 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dhrubajyoti","family":"Datta","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals, Cambridge, MA, 04142 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Egli","sequence":"additional","affiliation":[{"name":"Vanderbilt University, Department of Biochemistry, School of Medicine Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muthiah","family":"Manoharan","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals, Cambridge, MA, 04142 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V. Vinod","family":"Mootha","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center, Department of Ophthalmology, Dallas, TX 75235, USA"},{"name":"UT Southwestern Medical Center, Eugene McDermott Center for Human Growth and Development, Dallas, TX, 75235, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David R.","family":"Corey","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center, Departments of Pharmacology and Biochemistry, Dallas TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041100141090000_2025.03.11.642595v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad067"},{"key":"2026041100141090000_2025.03.11.642595v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2023.09.005"},{"key":"2026041100141090000_2025.03.11.642595v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-02105-y"},{"key":"2026041100141090000_2025.03.11.642595v1.4","doi-asserted-by":"publisher","DOI":"10.1021\/ja505986a"},{"key":"2026041100141090000_2025.03.11.642595v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2016.55"},{"key":"2026041100141090000_2025.03.11.642595v1.6","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2022.0021"},{"key":"2026041100141090000_2025.03.11.642595v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad415"},{"key":"2026041100141090000_2025.03.11.642595v1.8","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae368"},{"key":"2026041100141090000_2025.03.11.642595v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01334-x"},{"key":"2026041100141090000_2025.03.11.642595v1.10","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200241040-00002"},{"key":"2026041100141090000_2025.03.11.642595v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/NRD.2016.199"},{"key":"2026041100141090000_2025.03.11.642595v1.12","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-018-0983-6"},{"key":"2026041100141090000_2025.03.11.642595v1.13","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-022-01765-5"},{"key":"2026041100141090000_2025.03.11.642595v1.14","doi-asserted-by":"publisher","DOI":"10.3109\/13506129.2015.1015678"},{"key":"2026041100141090000_2025.03.11.642595v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2017.09.001"},{"key":"2026041100141090000_2025.03.11.642595v1.16","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X21666230623094710"},{"key":"2026041100141090000_2025.03.11.642595v1.17","doi-asserted-by":"crossref","unstructured":"Minnella, A.M. , Rissotto, R. , Antoniazzi, E. , Di Girolamo, M. , Luigetti, M. , Maceroni, M. , Bacherini, D. , Falsini, B. , Rizzo, S. and Obici, L. 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