Fabry Disease (FD) is a rare genetic disorder categorized as a lysosomal storage disease (LSD). It is caused by a deficiency in the activity of the lysosomal enzyme alpha-galactosidase A (α-GalA), leading to the accumulation of its metabolic substrate, globotriaosylceramide (GL3), and related glycosphingolipids in various organs of the body, including the heart, kidneys, pancreas, skin, lungs, and nervous system. This accumulation ultimately results in a range of organ-specific diseases, with severe cases potentially developing cardiovascular complications, end-stage renal disease, or even premature death.[1] However, due to the non-specific and rare nature of FD symptoms, it is typically diagnosed at a late stage, posing significant challenges for the diagnosis, prevention, treatment, and prognosis of the disease.

Genetic Mechanism of Fabry Disease (FD)

Fabry Disease (FD) is caused by mutations in the GLA gene located on the X chromosome. These mutations lead to reduced activity of the lysosomal enzyme alpha-galactosidase A (α-GalA). α-GalA is a crucial enzyme in the metabolism of globotriaosylceramide (GL3). When α-GalA is deficient, GL3 gradually accumulates in cells throughout the body, often associated with a high risk of early-onset stroke, arrhythmia, myocardial infarction or heart failure, and renal failure.[1]

There are two main clinical manifestations of FD: the early-onset (classic) form and the late-onset (attenuated) form. The early-onset form of FD is characterized by a nearly complete loss of α-GalA function and activity, leading to early and widespread multi-organ complications, which include acroparesthesia, abnormal sweating, corneal verticillata, angiokeratomas, as well as cardiovascular, cerebrovascular, and renal diseases such as cardiomyopathy, arrhythmias, stroke, and proteinuria. In contrast, the late-onset form of FD results from partially retained α-GalA activity, with the disease manifesting later and variably, largely depending on the residual level of α-GalA activity.[1-2]

Additionally, because the causative gene is located on the X chromosome, there is a significant sex difference in FD symptoms. Male patients typically exhibit more severe symptoms compared to female patients.

Figure 1. Pathophysiological Mechanism of Fabry Disease (FD): Lysosomal accumulation of glycosphingolipids in various cells is the cause of organ damage in Fabry Disease (FD).[2]

Development of Therapies for Fabry Disease (FD)

There are two main treatment methods for Fabry Disease (FD): enzyme replacement therapy (ERT) with intravenous infusions of agalsidase alpha or agalsidase beta every few weeks, and molecular chaperone therapy with daily oral administration of migalastat. However, the effectiveness of these treatments can be influenced by various factors, and the high cost of treatment (approximately €250,000 per year) makes it unaffordable for many patients.[3] Therefore, intensive research into the mechanisms of FD and the development of new, effective therapies are critical focuses of current research. Currently, over ten companies, including Abeona Therapeutics, UniQure, and Spark Therapeutics, are developing gene therapies mediated by adeno-associated virus (AAV) vectors.[4-5] These therapies deliver healthy copies of the GLA gene into the body using AAV vectors, enabling the gene to be transcribed and translated to produce functional α-Gal A enzyme. At least six AAV-hGLA gene therapies have entered clinical trial stages, offering new hope for the treatment of Fabry Disease (FD).

Figure 2. Therapeutic Strategy of AAV Gene Therapy 4D-310 for Fabry Disease (FD).[6]

Animal Models of Fabry Disease (FD)

AAV gene therapy is a significant research direction for new treatments for Fabry Disease (FD). During the development of these therapies, it is essential to evaluate the drug's efficacy and safety in animal models. Since FD is primarily caused by mutations in the GLA gene, leading to the loss of function and activity of the α-Gal A enzyme, Gla knockout mice (Gla-KO mice) have become the preferred model for preclinical evaluation of these therapies.

Currently, several therapies in clinical stages, including Freeline's FLT190 (Phase 2) [7], 4DMT's 4D-310 (Phase 1/2) [6, 8], UniQure's AMT-191 (Phase 1/2) [9], and Sangamo's ST-920 (Phase 1/2) [10-12], have all utilized Gla-KO mice for efficacy assessment. Additionally, companies like CANbridge and Genzyme are developing non-clinical stage AAV therapies [13-14] and are also using Gla-KO mice for evaluation. Therefore, Gla-KO mice are widely regarded as the "gold standard" disease model for FD, suitable for studying disease mechanisms and the preclinical efficacy evaluation of new therapies.

Figure 3. Gla-KO Mice (Fabry Mouse) Used for Preclinical Evaluation of AAV Gene Therapy ST-920.[11]

Cyagen's Gla-KO Mice Aid Preclinical Fabry Disease (FD) Research

Gla-KO mice accumulate globotriaosylceramide (GL3) in various cell types, a phenomenon that intensifies with age. The histological changes in these mice, including the nature and timing of substrate accumulation, closely resemble the pathophysiological process observed in Fabry disease patients.[15] Consequently, Gla-KO mice are widely used for the preclinical efficacy and safety evaluation of enzyme replacement therapy (ERT), AAV gene therapy, and substrate reduction therapy.

Cyagen’s Gla-KO mice (Product Code: S-KO-00955) are also extensively utilized for mechanism research and therapy evaluation. For example, studies have used liver-specific AAV therapy to treat Gla-KO mice (Orphanet J Rare Dis, 2023) [16], and to assess the effects and metabolism of novel ERT therapies (Biomolecules, 2022).[17] Additionally, a 2024 publication in Nature Cell Biology indicate how Gla-KO mice have contributed to uncovering the intrinsic link between lysosomal defects and innate immunity, as well as proposing new therapeutic strategies for lysosomal storage diseases (LSD).[18]

Figure 4. Cyagen's Gla-KO Mice (FD) Aid in Preclinical Research of AAV Gene Therapy.[16]

Recommended Fabry Mouse Disease Models

Given the variety of research models that could be used to study the mechanisms of Fabry Disease (FD) and evaluate potential therapeutics, Cyagen has developed several Fabry mouse models for FD research currently available through the Cyagen Knockout Catalog Models repository. Our Fabry Disease Mouse Models include Gla-KO mice (across both the C57BL/6NCya and C57BL/6JCya strain backgrounds) and Gla conditional knockout mice (Gla-CKO, Gla-Flox), also known as Gla floxed mice.

These FD mouse models have been used in preclinical research with promising results from phenotypic presentation to therapeutic evaluations. Notably, Cyagen’s C57BL/6N Gla-KO Mice have demonstrated the accumulation of Gb3 and lyso-Gb3 in various tissues, exhibiting the phenotypes necessary in FD model mice.[17] Beyond this, our Gla-KO FD model mice have been used in preclinical feasibility studies of potential treatments, providing favorable therapeutic results for both an AAV2/8-hGLA gene therapy [16] and enzyme replacement therapy (ERT) with a recombinant enzyme (Lanzyme) based on a CHO-S cell system to provide new potential options for FD therapy.[17]

Cyagen can also provide comprehensive genetic engineering services for custom cell and animal model projects for your research. Contact us for a free consultation on your research model(s).

Fabry Mouse Models: Knockout and Floxed Gla

Product Description  Product Number Strain Name  Strain Number Link
B/6N Gla-KO Mice S-KO-00955  C57BL/6NCya-Glaem1/Cya KOCMP-11605-Gla-B6N-VA Learn More>>
B/6J Gla-KO Mice S-KO-00956  C57BL/6JCya-Glaem1/Cya KOCMP-11605-Gla-B6J-VA Learn More>>  
B/6N Gla-CKO Mice S-CKO-01100 C57BL/6JCya-Glaem1flox/Cya CKOCMP-11605-Gla-B6J-VA Learn More>>

Save 20-30% on KO/cKO Models until June 30, 2024

The Spring into Science event offers researchers a limited time to save 20-30% off KO/cKO models and receive free Cre models for cKO mice. Choose between our KO and cKO Mouse Model Special Offers, and simply click on your preferred option to place your order and submit your contact information.

Ask us for more information about discounts on our downstream breeding options, including additional options for heterozygous, homozygous, and floxed deliverables, as well as our phenotype analysis and preclinical evaluation services, including in vivo efficacy evaluations.

Need a custom Cre line? Purchase a cKO model and let Cyagen develop custom CRISPR-engineered Cre lines for your project for 50% off!

[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]Domm JM, Wootton SK, Medin JA, West ML. Gene therapy for Fabry disease: Progress, challenges, and outlooks on gene-editing. Mol Genet Metab. 2021 Sep-Oct;134(1-2):117-131.
[5]Rodríguez-Castejón J, Beraza-Millor M, Solinís MÁ, Rodríguez-Gascón A, Del Pozo-Rodríguez A. Targeting strategies with lipid vectors for nucleic acid supplementation therapy in Fabry disease: a systematic review. Drug Deliv Transl Res. 2024 Apr 8.
[6]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)
[7]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.
[8]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.
[9]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
[10]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.
[11]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.
[12]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.
[13]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)
[14]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.
[15]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.
[16]Deng M, Zhou H, He S, Qiu H, Wang Y, Zhao AY, Mu Y, Li F, Zhao AZ. Systematic gene therapy derived from an investigative study of AAV2/8 vector gene therapy for Fabry disease. Orphanet J Rare Dis. 2023 Sep 5;18(1):275. 
[17]Deng M, Zhou H, Liang Z, Li Z, Wang Y, Guo W, Zhao AY, Li F, Mu Y, Zhao AZ. Development of Lanzyme as the Potential Enzyme Replacement Therapy Drug for Fabry Disease. Biomolecules. 2022 Dec 27;13(1):53.
[18]Wang A, Chen C, Mei C, Liu S, Xiang C, Fang W, Zhang F, Xu Y, Chen S, Zhang Q, Bai X, Lin A, Neculai D, Xia B, Ye C, Zou J, Liang T, Feng XH, Li X, Shen C, Xu P. Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders. Nat Cell Biol. 2024 Feb;26(2):219-234.