{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T16:31:52Z","timestamp":1788539512626,"version":"build-2803163510"},"reference-count":27,"publisher":"SAGE Publications","issue":"13-14","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"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":[[2025,7]]},"abstract":"<jats:p>\n                    The low-density lipoprotein receptor (LDLR) plays a crucial role in cholesterol regulation and lipoprotein transport. Variations in the\n                    <jats:italic toggle=\"yes\">LDLR<\/jats:italic>\n                    gene can cause familial hypercholesterolemia (FH), with homozygous familial hypercholesterolemia (HoFH) being the most severe form. HoFH is marked by elevated low-density lipoprotein cholesterol (LDL-C) levels and early onset of cardiovascular disease, often with a poor prognosis. Current treatment options for HoFH are limited by insufficient effectiveness and restricted availability. Gene therapy, which involves the delivery of functional\n                    <jats:italic toggle=\"yes\">LDLR<\/jats:italic>\n                    genes, offers a promising and innovative approach that could significantly improve outcomes for patients with HoFH. In this study, the adeno-associated virus serotype 8 (AAV8) vector was used to deliver the\n                    <jats:italic toggle=\"yes\">LDLR<\/jats:italic>\n                    gene specifically to hepatocytes. The vector was designed using the pAAV-TBG plasmid, incorporating a hepatocyte-specific thyroid hormone-binding globulin (TBG) promoter. Viral packaging was performed in HEK 293T cells, followed by virus collection, purification, and titration. Mice, including C57BL\/6J,\n                    <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n                    -KO, and homozygous\n                    <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n                    p.W483X mice, were injected with low, medium, or high doses of the virus via the tail vein. The efficacy and safety of the AAV8-\n                    <jats:italic toggle=\"yes\">LDLR<\/jats:italic>\n                    gene therapy were assessed through Western blot analysis, lipid profiling, and liver pathology. AAV8-mediated\n                    <jats:italic toggle=\"yes\">LDLR<\/jats:italic>\n                    delivery effectively improved lipid levels in both\n                    <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n                    -KO and homozygous\n                    <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n                    p.W483X mice. LDL-C levels showed a sustained reduction over the 2-month observation period. Western blot analysis confirmed the expression of LDLR protein in the liver, while lipid profiling demonstrated significant reductions in total cholesterol, triglycerides, LDL-C, and high-density lipoprotein cholesterol levels. Liver histopathology revealed no significant differences in non-alcoholic fatty liver disease scores between groups, indicating a favorable safety profile, particularly at low and medium doses. AAV8-\n                    <jats:italic toggle=\"yes\">LDLR<\/jats:italic>\n                    gene therapy shows considerable promise as an effective treatment for HoFH. Our results indicate that this therapy significantly reduces lipid levels while maintaining a favorable safety profile.\n                  <\/jats:p>","DOI":"10.1089\/hum.2024.164","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T04:35:09Z","timestamp":1749011709000},"page":"976-988","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["AAV8-\n                    <i>LDLR<\/i>\n                    Gene Therapy in\n                    <i>Ldlr<\/i>\n                    -KO and Homozygous\n                    <i>Ldlr<\/i>\n                    p.W483X Mice"],"prefix":"10.1177","volume":"36","author":[{"given":"Qingao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muyun","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Jin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"Department of Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gengchen","family":"Su","sequence":"additional","affiliation":[{"name":"School of Medicine, Tsinghua University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine, Tsinghua University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaide","family":"Ju","sequence":"additional","affiliation":[{"name":"School of Medicine, Tsinghua University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1532-0029","authenticated-orcid":false,"given":"Shuyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Luan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"Department of Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.19.1.141"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2481"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.93"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.118.033470"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.03.057"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurjpc\/zwae144"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehad197"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.5551\/jat.CR003"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1080\/14656566.2017.1340941"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2004215"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2019.02.001"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.5551\/jat.RV17029"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0012-9"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0494-335"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1195-1148"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.554"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2018.10.012"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.70014"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2024.108720"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.03.045"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.182412299"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2022.06.004"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2020.06.026"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.4103\/0976-0105.177703"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07-9574LSF"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-008-9416-z"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-018-0052-6"}],"container-title":["Human 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