{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T18:01:12Z","timestamp":1781632872451,"version":"3.54.5"},"reference-count":31,"publisher":"SAGE Publications","issue":"21-22","license":[{"start":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T00:00:00Z","timestamp":1667260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T00:00:00Z","timestamp":1667260800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:p>\n                    Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by transthyretin (TTR) amyloid fibril accumulation in tissues, which disrupts organ function. As the TTR protein is primarily synthesized by the liver, liver transplantation can cure familial ATTR but is not an option for the predominant age-related wild-type ATTR. Approved treatment approaches include TTR stabilizers and an RNA-interference therapeutic, but these require regular re-administration. Gene editing could represent an effective one-time treatment. We evaluated adeno-associated virus (AAV) vector-delivered, gene-editing meganucleases to reduce TTR levels. We used engineered meganucleases targeting two different sites within the\n                    <jats:italic toggle=\"yes\">TTR<\/jats:italic>\n                    gene. AAV vectors expressing TTR meganuclease transgenes were first tested in immunodeficient mice expressing the human\n                    <jats:italic toggle=\"yes\">TTR<\/jats:italic>\n                    sequence delivered using an AAV vector and then against the endogenous\n                    <jats:italic toggle=\"yes\">TTR<\/jats:italic>\n                    gene in rhesus macaques. Following a dose of 3\u2009\u00d7\u200910\n                    <jats:sup>13<\/jats:sup>\n                    genome copies per kilogram, we detected on-target editing efficiency of up to 45% insertions and deletions (indels) in the TTR genomic DNA locus and &gt;80% indels in\n                    <jats:italic toggle=\"yes\">TTR<\/jats:italic>\n                    RNA, with a concomitant decrease in serum TTR levels of &gt;95% in macaques. The significant reduction in serum TTR levels following\n                    <jats:italic toggle=\"yes\">TTR<\/jats:italic>\n                    gene editing indicates that this approach could be an effective treatment for ATTR.\n                  <\/jats:p>","DOI":"10.1089\/hum.2022.061","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T11:20:55Z","timestamp":1769080855000},"page":"1174-1186","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Treating Transthyretin Amyloidosis via Adeno-Associated Virus Vector Delivery of Meganucleases"],"prefix":"10.1177","volume":"33","author":[{"given":"Jenny A.","family":"Greig","sequence":"first","affiliation":[{"name":"Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilo","family":"Breton","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott N.","family":"Ashley","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly M.","family":"Martins","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra","family":"Gorsuch","sequence":"additional","affiliation":[{"name":"Precision BioSciences, Inc., Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna K.","family":"Chorazeczewski","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Furmanak","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Perelman School 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, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bell","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Shoop","sequence":"additional","affiliation":[{"name":"Precision BioSciences, Inc., Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Precision BioSciences, Inc., Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Smith","sequence":"additional","affiliation":[{"name":"Precision BioSciences, Inc., Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginger","family":"Tomberlin","sequence":"additional","affiliation":[{"name":"Precision BioSciences, Inc., Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Clark","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-3964","authenticated-orcid":false,"given":"Elizabeth L.","family":"Buza","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanying","family":"Yan","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Jantz","sequence":"additional","affiliation":[{"name":"Precision BioSciences, Inc., Durham, North Carolina, 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, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.3109\/07853890.2015.1068949"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.1371"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.018852"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1185\/03007995.2012.754348"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.03.596"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2015-310907"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/jns.12153"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/lt.24058"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1121005109"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1805689"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-013-7051-7"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1716153"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/ene.14285"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1080\/13506129.2016.1191458"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1716793"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.02.014"},{"key":"e_1_3_6_18_2","unstructured":"Wood 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Development of NTLA-2001 a CRISPR-Cas9 genome editing therapeutic for the treatment of ATTR. In: Presented at the Second European Congress for ATTR Amyloidosis. Berlin; September 1\u20133 2019."},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107454"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4182"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2021.02.020"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.12.028"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2005.08.017"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0112268"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1086\/595830"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1089\/hgtb.2018.038"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3117"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-020-6655-4"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2006.03.008"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2011.031"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1089\/humc.2016.048"},{"key":"e_1_3_6_32_2","unstructured":"Alnylam. Alnylam Reports Positive Topline Results from HELIOS-A Phase 3 Study of Vutrisiran in Patients with hATTR Amyloidosis with Polyneuropathy. Cambridge MA; 2021. Available from: https:\/\/investors.alnylam.com\/press-release?id=25366 [Last accessed: July 6 2022]."}],"container-title":["Human Gene Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2022.061","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/hum.2022.061","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2022.061","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:56:18Z","timestamp":1777449378000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/hum.2022.061"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11]]},"references-count":31,"journal-issue":{"issue":"21-22","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["10.1089\/hum.2022.061"],"URL":"https:\/\/doi.org\/10.1089\/hum.2022.061","relation":{},"ISSN":["1043-0342","1557-7422"],"issn-type":[{"value":"1043-0342","type":"print"},{"value":"1557-7422","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11]]}}}