智鼠故事 
Gla KO小鼠
复苏/繁育服务
产品名称
Gla KO
产品编号
I001223
品系全称
C57BL/6NCya-Glaem1/Cya
品系背景
C57BL/6NCya
品系状态
使用本品系发表的文献需注明： Gla KO mice (Catalog I001223) were purchased from Cyagen.
交付类型
周龄
性别
基因型
数量
品系介绍
法布雷病（Fabry Disease, FD）是一种由X染色体上GLA基因突变引起的罕见遗传性溶酶体贮存病，导致溶酶体半乳糖苷酶A（α-GalA）活性缺乏。α-GalA的缺失会引起代谢底物三己糖酰基鞘脂醇（GL3）在多个器官中积聚，最终导致器官损伤，严重情况下可能引发心脑血管并发症、终末期肾病，甚至早逝 [1]。临床上，FD分为早发型（典型型）和衰减型（晚发型）。早发型患者几乎完全丧失α-GalA功能，早期即出现多器官损伤；衰减型患者则保留部分酶活性，症状的轻重取决于残存酶活水平 [1-2]。由于GLA基因位于X染色体上，男性患者通常症状更为严重。当前，FD的治疗方法主要包括酶替代疗法（ERT）和分子伴侣疗法（Migalastat），但由于费用高昂且疗效受多种因素限制，亟需开发新的治疗手段 [3]。在临床前研究中，Gla基因敲除小鼠（Gla-KO）已成为研究FD机制及评估疗法的“金标准” [4]。该模型在多种组织中随着年龄增长出现GL3积聚，其组织学变化高度模拟了人类FD患者的病理特征，被广泛用于酶替代疗法、AAV基因疗法和底物减少疗法等研究 [5-13]。
本品系为Gla基因敲除（KO）小鼠，是通过基因编辑技术敲除小鼠X染色体上的Gla基因（人类GLA基因的小鼠同源基因）构建的法布雷病研究模型。Gla基因的缺失导致该小鼠体内缺乏Gla基因表达及溶酶体半乳糖苷酶A（α-GalA）活性。本模型可用于解析法布雷病的疾病机制、评估治疗方法的有效性和安全性，以及研究溶酶体相关代谢异常及其病理生理影响。
参考文献
Chan B, Adam DN. A Review of Fabry Disease. Skin Therapy Lett. 2018 Mar;23(2):4-6.
Lerario S, Monti L, Ambrosetti I, Luglio A, Pietra A, Aiello V, Montanari F, Bellasi A, Zaza G, Galante A, Salera D, Capelli I, La Manna G, Provenzano M. Fabry disease: a rare disorder calling for personalized medicine. Int Urol Nephrol. 2024 Apr 13.
Lenders M, Brand E. Fabry disease - a multisystemic disease with gastrointestinal manifestations. Gut Microbes. 2022 Jan-Dec;14(1):2027852.
Ohshima T, Murray GJ, Swaim WD, Longenecker G, Quirk JM, Cardarelli CO, Sugimoto Y, Pastan I, Gottesman MM, Brady RO, Kulkarni AB. alpha-Galactosidase A deficient mice: a model of Fabry disease. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2540-4.
4D molecular therapeutics. An Open-label, Phase 1/2 Trial of Gene Therapy 4D-310 in Adult Males with Fabry Disease. Retrieved April 18, 2024, from 4DMT PPT Template (4dmoleculartherapeutics.com)
Jeyakumar JM, Kia A, Tam LCS, McIntosh J, Spiewak J, Mills K, Heywood W, Chisari E, Castaldo N, Verhoef D, Hosseini P, Kalcheva P, Cocita C, Miranda CJ, Canavese M, Khinder J, Rosales C, Hughes D, Sheridan R, Corbau R, Nathwani A. Preclinical evaluation of FLT190, a liver-directed AAV gene therapy for Fabry disease. Gene Ther. 2023 Jun;30(6):487-502.
Shen JS, Arning E, West ML, Day TS, Chen S, Meng XL, Forni S, McNeill N, Goker-Alpan O, Wang X, Ashcraft P, Moore DF, Cheng SH, Schiffmann R, Bottiglieri T. Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease. Hum Mol Genet. 2017 Mar 15;26(6):1182-1192.
uniQure. Patient enrollment in the clinical trial of AMT-191, uniQure’s gene therapy candidate for the treatment of Fabry disease, is expected to begin in the first half of 2024. Retrieved April 18, 2024, from Fabry Disease | Programs & Pipeline | uniQure
Pagant S, Huston MW, Moreira L, Gan L, St Martin S, Sproul S, Holmes MC, Meyer K, Wechsler T, Desnick RJ, Yasuda M. ZFN-mediated in vivo gene editing in hepatocytes leads to supraphysiologic α-Gal A activity and effective substrate reduction in Fabry mice. Mol Ther. 2021 Nov 3;29(11):3230-3242.
Yasuda M, Huston MW, Pagant S, Gan L, St Martin S, Sproul S, Richards D, Ballaron S, Hettini K, Ledeboer A, Falese L, Cao L, Lu Y, Holmes MC, Meyer K, Desnick RJ, Wechsler T. AAV2/6 Gene Therapy in a Murine Model of Fabry Disease Results in Supraphysiological Enzyme Activity and Effective Substrate Reduction. Mol Ther Methods Clin Dev. 2020 Jul 9;18:607-619.
Takahashi H, Hirai Y, Migita M, Seino Y, Fukuda Y, Sakuraba H, Kase R, Kobayashi T, Hashimoto Y, Shimada T. Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13777-82.
PR Newswire. CANbridge Pharmaceuticals to Present Fabry Disease Gene Therapy Abstract at ESGCT 30th Annual Congress. Retrieved April 18, 2024, from CANbridge Pharmaceuticals to Present Fabry Disease Gene Therapy Abstract at ESGCT 30th Annual Congress (prnewswire.com)
Ziegler RJ, Cherry M, Barbon CM, Li C, Bercury SD, Armentano D, Desnick RJ, Cheng SH. Correction of the Biochemical and Functional Deficits in Fabry Mice Following AAV8-mediated Hepatic Expression of α-galactosidase A. Mol Ther. 2007 Mar;15(3):492-500.
构建方案
通过基因编辑技术敲除了小鼠X染色体上的Gla基因2~5号外显子区域。
图1. Gla KO 小鼠基因编辑策略。
