智鼠故事 
B6-hATP7B小鼠
复苏/繁育服务
产品名称
B6-hATP7B
产品编号
I001130
品系全称
C57BL/6NCya-Atp7btm1(hATP7B)/Cya
品系背景
C57BL/6NCya
补充
本产品为HUGO-GT® (Humanized Genomic Ortholog for Gene Therapy) 系列小鼠
使用本品系发表的文献需注明： B6-hATP7B mice (Catalog I001130) were purchased from Cyagen.
产品类型
周龄
性别
基因型
数量
品系介绍
肝豆状核变性（Hepatolenticular degeneration，HLD）又称为威尔逊病（Wilson’s disease，WD），是一种可导致肝功能衰竭的常染色体隐性铜转运障碍性疾病，发病率约为1:30,000 [1]。肝豆状核变性的临床表现主要包括慢性肝脏损害、神经和精神症状，偶可引起急性肝衰竭、溶血性贫血，其典型表现是在青春期或成年早期合并肝脏疾病和运动障碍，但患者的表型差异变化较大，多达60%的患者在发病时伴有神经或精神症状 [2]。研究表明，ATP7B基因的突变与肝豆状核变性有关，其特点是随着功能性ATP7B蛋白质的缺失，体内多余铜的清除受到影响而导致铜积累到毒性水平，损害肝脏和大脑等组织和器官 [1, 3-4]。ATP7B基因编码的铜离子转运ATP酶β肽是P型阳离子转运ATP酶家族的成员，该家族利用三磷酸腺苷（ATP）分子中储存的能量将金属运入和运出细胞。ATP7B蛋白由多个跨膜结构域、一个ATP酶共识序列、一个铰链结构域、一个磷酸化位点以及至少2个假定的铜结合位点等组成 [5]。该蛋白主要存在于肝脏，少量存在于肾脏和大脑，其作为铜转运ATP酶，在将铜从肝脏运送到身体其他部位方面发挥着作用。
肝豆状核变性（HLD）的治疗方法主要包括药物治疗和手术治疗。药物治疗旨在减轻症状、延缓疾病进展并预防并发症，而手术治疗通常为肝移植。随着对肝豆状核变性基因病因的深入研究，定向基因治疗有望成为新兴的治疗策略。目前，多家生物技术公司和科研机构，如Prime Medicine和LogicBio Therapeutics，正致力于开发基于CRISPR/Cas9、Prime Editor或其他基因编辑技术的疗法，以期纠正或替换突变的ATP7B基因。这些疗法前景广阔，目前正处于临床前研究阶段 [6-15]。由于基因编辑疗法需精确靶向人源ATP7B基因，将小鼠基因人源化修饰将有助于加速基因疗法进入临床应用。本品系是小鼠Atp7b基因人源化模型，可用于肝豆状核变性的致病机制研究，该模型纯合子是可存活且可育的。此外，基于自主研发的TurboKnockout融合BAC重组的技术创新，赛业生物还可提供基于该模型构建的热门点突变疾病模型，也可针对不同点突变提供定制服务。
参考文献
Panagiotakaki E, Tzetis M, Manolaki N, Loudianos G, Papatheodorou A, Manesis E, Nousia-Arvanitakis S, Syriopoulou V, Kanavakis E. Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004 Dec 1;131(2):168-73.
Shribman S, Poujois A, Bandmann O, Czlonkowska A, Warner TT. Wilson's disease: update on pathogenesis, biomarkers and treatments. J Neurol Neurosurg Psychiatry. 2021 Oct;92(10):1053-1061.
Ferenci, P. Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing. Hum Genet 120, 151–159 (2006).
Fatemi N, Sarkar B. Molecular mechanism of copper transport in Wilson disease. Environ Health Perspect. 2002 Oct;110 Suppl 5(Suppl 5):695-8. doi: 10.1289/ehp.02110s5695.
Cater MA, Forbes J, La Fontaine S, Cox D, Mercer JF. Intracellular trafficking of the human Wilson protein: the role of the six N-terminal metal-binding sites. Biochem J. 2004 Jun 15;380(Pt 3):805-13.
Pfizer. (2021, August 12). VTX-801 Receives U.S. FDA Fast Track Designation for the Treatment of Wilson Disease. Retrieved January 22, 2022, from
https://www.pfizer.com/news/press-release/press-release-detail/vtx-801-receives-us-fda-fast-track-designation-treatment
https://www.pfizer.com/news/press-release/press-release-detail/vtx-801-receives-us-fda-fast-track-designation-treatment
Choi W, Cha S, Kim K. Navigating the CRISPR/Cas Landscape for Enhanced Diagnosis and Treatment of Wilson's Disease. Cells. 2024 Jul 18;13(14):1214.
Prime Medicine. (2024). AASLD WD Talk. Retrieved February 21, 2025, from
https://primemedicine.com/wp-content/uploads/2024/12/2024-11-18-AASLD-WD-Talk-v3_Final_PDF.pdf
https://primemedicine.com/wp-content/uploads/2024/12/2024-11-18-AASLD-WD-Talk-v3_Final_PDF.pdf
Yuan Q, Zeng H, Daniel TC, Liu Q, Yang Y, Osikpa EC, Yang Q, Peddi A, Abramson LM, Zhang B, Xu Y, Gao X. Orthogonal and multiplexable genetic perturbations with an engineered prime editor and a diverse RNA array. Nat Commun. 2024 Dec 30;15(1):10868. doi: 10.1038/s41467-024-55134-9.
Liu L, Cao J, Chang Q, Xing F, Yan G, Fu L, Wang H, Ma Z, Chen X, Li Y, Li S. In Vivo Exon Replacement in the Mouse Atp7b Gene by the Cas9 System. Hum Gene Ther. 2019 Sep;30(9):1079-1092.
Wei R, Yang J, Cheng CW, Ho WI, Li N, Hu Y, Hong X, Fu J, Yang B, Liu Y, Jiang L, Lai WH, Au KW, Tsang WL, Tse YL, Ng KM, Esteban MA, Tse HF. CRISPR-targeted genome editing of human induced pluripotent stem cell-derived hepatocytes for the treatment of Wilson's disease. JHEP Rep. 2021 Oct 30;4(1):100389.
Padula A, Spinelli M, Nusco E, Bujanda Cundin X, Capolongo F, Campione S, Perna C, Bastille A, Ericson M, Wang CC, Zhang S, Amoresano A, Nacht M, Piccolo P. Genome editing without nucleases confers proliferative advantage to edited hepatocytes and corrects Wilson disease. JCI Insight. 2023 Nov 8;8(21):e171281.
Pöhler M, Guttmann S, Nadzemova O, Lenders M, Brand E, Zibert A, Schmidt HH, Sandfort V. CRISPR/Cas9-mediated correction of mutated copper transporter ATP7B. PLoS One. 2020 Sep 30;15(9):e0239411.
Schene IF, Joore IP, Oka R, Mokry M, van Vugt AHM, van Boxtel R, van der Doef HPJ, van der Laan LJW, Verstegen MMA, van Hasselt PM, Nieuwenhuis EES, Fuchs SA. Prime editing for functional repair in patient-derived disease models. Nat Commun. 2020 Oct 23;11(1):5352.
Ultragenyx. (n.d.). UX701 for Wilson Disease. Retrieved January 22, 2022, from
https://www.ultragenyx.com/our-research/pipeline/ux701-for-wilson-disease/
https://www.ultragenyx.com/our-research/pipeline/ux701-for-wilson-disease/
构建方案
将小鼠Atp7b基因编码内源结构域的序列替换为人源ATP7B基因编码结构域的序列。
图1. B6-hATP7B小鼠基因编辑打靶示意图。
