{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T12:25:20Z","timestamp":1789129520331,"version":"build-2803163510"},"reference-count":25,"publisher":"SAGE Publications","issue":"19-20","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Precision BioSciences"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:p>\n                    Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (\n                    <jats:italic toggle=\"yes\">AGXT<\/jats:italic>\n                    ) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the\n                    <jats:italic toggle=\"yes\">HAO1<\/jats:italic>\n                    gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and\n                    <jats:italic toggle=\"yes\">\n                      Agxt\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice, a mouse model of PH1. We observed &gt;30% editing of\n                    <jats:italic toggle=\"yes\">HAO1<\/jats:italic>\n                    in\n                    <jats:italic toggle=\"yes\">\n                      Agxt\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated\n                    <jats:italic toggle=\"yes\">in\u00a0vivo<\/jats:italic>\n                    targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target\n                    <jats:italic toggle=\"yes\">HAO1<\/jats:italic>\n                    in mice and nonhuman primates to achieve high levels of\n                    <jats:italic toggle=\"yes\">HAO1<\/jats:italic>\n                    gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.\n                  <\/jats:p>","DOI":"10.1177\/10430342261460681","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T07:41:59Z","timestamp":1781595719000},"page":"963-974","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>In Vivo<\/i>\n                    Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1"],"prefix":"10.1177","volume":"37","author":[{"given":"Jenny A.","family":"Greig","sequence":"first","affiliation":[{"name":"Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilo","family":"Breton","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie K.","family":"Smith","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Furmanak","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bell","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Clark","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9630-3131","authenticated-orcid":false,"given":"James M.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"e_1_3_4_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(86)80563-4"},{"key":"e_1_3_4_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2012.03.004"},{"key":"e_1_3_4_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1301564"},{"key":"e_1_3_4_5_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V1291986"},{"key":"e_1_3_4_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/ckj\/sfab232"},{"key":"e_1_3_4_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2015.107"},{"key":"e_1_3_4_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021712"},{"key":"e_1_3_4_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.2c00110"},{"key":"e_1_3_4_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07827-1"},{"key":"e_1_3_4_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2022.03.006"},{"key":"e_1_3_4_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4182"},{"key":"e_1_3_4_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2021.02.020"},{"key":"e_1_3_4_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.12.028"},{"key":"e_1_3_4_15_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2022.061"},{"key":"e_1_3_4_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2016.4"},{"key":"e_1_3_4_17_1","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2016030338"},{"key":"e_1_3_4_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2005.08.017"},{"key":"e_1_3_4_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0112268"},{"key":"e_1_3_4_20_1","doi-asserted-by":"publisher","DOI":"10.1086\/595830"},{"key":"e_1_3_4_21_1","doi-asserted-by":"publisher","DOI":"10.1089\/hgtb.2018.038"},{"key":"e_1_3_4_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3117"},{"key":"e_1_3_4_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-020-6655-4"},{"key":"e_1_3_4_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2006.03.008"},{"key":"e_1_3_4_25_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102529"},{"key":"e_1_3_4_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-017-3741-1"}],"container-title":["Human Gene Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10430342261460681","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/10430342261460681","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10430342261460681","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T11:17:53Z","timestamp":1789125473000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/10430342261460681"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,16]]},"references-count":25,"journal-issue":{"issue":"19-20","published-print":{"date-parts":[[2026,10,1]]}},"alternative-id":["10.1177\/10430342261460681"],"URL":"https:\/\/doi.org\/10.1177\/10430342261460681","relation":{},"ISSN":["1043-0342","1557-7422"],"issn-type":[{"value":"1043-0342","type":"print"},{"value":"1557-7422","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,16]]}}}