Gla KO Mice

Catalog Number: I001223

Strain Name: C57BL/6NCya-Glaem1/Cya

Genetic Background: C57BL/6NCya

 

Strain Description

Fabry Disease (FD) is a rare genetic lysosomal storage disorder caused by mutations in the GLA gene on the X chromosome, leading to a deficiency in lysosomal α-galactosidase A (α-GalA) activity. The absence of α-GalA results in the accumulation of the metabolic substrate globotriaosylceramide (GL3) in multiple organs, ultimately causing organ damage. In severe cases, this may lead to cardiovascular complications, end-stage renal disease, and even early death [1]. Clinically, FD is divided into early-onset (typical) and late-onset (attenuated) forms. Early-onset patients almost completely lose α-GalA activity and experience multi-organ damage early in life, while late-onset patients retain some enzyme activity, with symptom severity dependent on the residual enzyme activity [1-2]. Since the GLA gene is located on the X chromosome, male patients typically experience more severe symptoms. Current treatment options include enzyme replacement therapy (ERT) and molecular chaperone therapy (migalastat), but due to high costs and various limitations on efficacy, new therapeutic strategies are urgently needed [3]. In preclinical studies, Gla knockout (KO) mice have become the "gold standard" for studying the mechanisms of FD and evaluating therapies [4]. Gla KO mice exhibit GL3 accumulation in various tissues with aging, and its histological changes closely mimic the pathological features seen in human FD patients. It is widely used in research on enzyme replacement therapy, AAV gene therapy, and substrate reduction therapy [5-13].

This strain is a Gla gene knockout (KO) mouse model of Fabry Disease, created using gene editing technology to knockout the Gla gene on the X chromosome of mice (the homolog of the human GLA gene). The deletion of the Gla gene results in the absence of Gla gene expression and α-GalA activity. This model can be widely used for studying the mechanisms of Fabry Disease, assessing the efficacy and safety of potential therapies, and investigating lysosomal-related metabolic disorders and their pathophysiological effects.

Strain Strategy


Figure 1. Gene editing strategy of Gla KO mice. The 2nd to 5th exonic regions of the Gla gene in the mouse X chromosome was knocked out using gene editing technology.

Strain Application

  • Mechanistic studies and therapeutic evaluations of Fabry Disease (FD)
  • Research on α-GalA function and related metabolic pathways
  • Studies on lysosomal structure and function, and exploration of diseases caused by lysosomal defects.

 

Validation Data

1. Gene Expression Analysis


Figure 2. Gene expression analysis of the Gla gene in various tissues of wild-type (WT) and male Gla KO mice (Gla-/Y). RT-qPCR results show that, compared to wild-type mice, no Gla gene expression was detected in the heart, liver, kidney, brain, or skin tissues of the Gla KO mice, confirming the successful knockout of the gene.

 

References
[1]Chan B, Adam DN. A Review of Fabry Disease. Skin Therapy Lett. 2018 Mar;23(2):4-6.
[2]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.
[3]Lenders M, Brand E. Fabry disease - a multisystemic disease with gastrointestinal manifestations. Gut Microbes. 2022 Jan-Dec;14(1):2027852.
[4]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.
[5]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)
[6]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.
[7]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.
[8]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
[9]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.
[10]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.
[11]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.
[12]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)
[13]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.