What is Fabry Disease?

Fabry Disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by mutations in the GLA gene, leading to a spectrum of symptoms. The estimated incidence of Fabry Disease is approximately 1 in 100,000.

Fabry Disease is classified into two forms: Classic and Non-Classical (Later-Onset). The Classic form typically manifests symptoms in childhood or adolescence, affecting males earlier and more severely. Symptoms include neuropathic pain, acroparesthesia, episodic "Fabry crises" of acute pain, and later progression to severe cardiac, renal, and cerebrovascular complications. The Non-Classical form presents later in life (40-60 years) and commonly features cardiac disease (cardiomegaly, left ventricular hypertrophy, cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction) and renal disease (end-stage renal disease).

 

(Image: Major Symptoms of Fabry Disease - PubMed)

Pathogenesis
 

Fabry Disease is caused by mutations in the GLA gene located at Xq22.1. These mutations result in reduced or completely absent activity of the enzyme α-galactosidase A (α-Gal A). This enzymatic deficiency leads to massive accumulation of the metabolic substrate globotriaosylceramide (GL-3, also known as Gb3) and its deacylated derivative, lyso-GL-3 (lyso-Gb3), within tissue cells, causing corresponding multi-organ dysfunction and potentially death.

Specific GLA gene mutations, such as c.337T>C (p.F113L), p.N215S, p.M296I, p.R301Q, p.G328R, and IVS4+919G>A, are associated with the late-onset cardiac phenotype of Fabry Disease.

(Image: PubMed)

Gene Therapy
 

1. Adeno-Associated Virus (AAV) Vectors: Use AAV vectors to deliver a functional GLA gene to patients, aiming to replace or repair the mutated gene. AAV vectors can efficiently and safely deliver the gene to the liver, minimizing immune reactions and toxicity.

2. Hematopoietic Stem/Progenitor Cells (HSPCs): Use lentiviral vectors to introduce the GLA gene into hematopoietic stem cells (HSPCs) ex vivo, which are then reinfused into the patient. This approach aims to provide long-term correction of disease progression, potentially reducing or eliminating the need for retreatment.

3. mRNA Therapy: Involves delivering mRNA encoding normal α-Gal A, enabling its translation into functional protein within patient cells.

4. Gene Editing: Utilizes gene editing technologies to delete pathogenic genomic segments, insert corrective genes into precise locations, or perform base-pair conversions.
 

Mouse Models
 

● GLA KO Mice: Knockout of the GLA gene, modeling the core pathological feature of Fabry Disease: the accumulation of glycosphingolipids (like GL-3/Gb3) in multiple organs due to loss of enzyme function.

● G3S/GLA KO Mice: In a GLA knockout background, these mice overexpress human globotriaosylceramide synthase (G3S). This significantly accelerates the accumulation of glycosphingolipid substrates (e.g., GL-3/Gb3) in organs, resulting in a more severe pathological phenotype that more closely resembles human Fabry Disease compared to GLA KO mice alone.

● IVS4+919G>A Mutation Mice: Model the IVS4+919G>A mutation in the GLA gene, which is associated with the late-onset cardiac phenotype in Fabry Disease.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various FD mouse models according to client needs, such as GLA KO mice, G3S/GLA KO mice, and IVS4+919G>A mutation mice. We welcome inquiries!

 

References:

[1] Ouyang Yan, Ren Hong, Chen Nan. Research Progress in the Precision Treatment of Fabry Disease. Chinese Journal of Nephrology, 2023, 39(4): 298-304. DOI: 10.3760/cma.j.cn441217-20220831-00850.

[2] Borisch, C., Thum, T., Bär, C. et al. Human in vitro models for Fabry disease: new paths for unravelling disease mechanisms and therapies. J Transl Med 22, 965 (2024). https://doi.org/10.1186/s12967-024-05756-w

[3] Ruangsiriluk, W.; Deshpande, M.; Boukharov, N.; Rajarshi, G.; Mukherji, S.; Yuan, S.; Wiseman, J.; Chen, N.; Park, E.; Cho, H.; et al. Reversing Pathology in an Aggravated Fabry Mouse Model Using Low-Dose Engineered Human Alpha-Galactosidase A AAV Gene Therapy. Biomedicines 2025, 13, 577. https://doi.org/10.3390/biomedicines13030577

[4] Sorriento D, Iaccarino G. The Cardiovascular Phenotype in Fabry Disease: New Findings in the Research Field. Int J Mol Sci. 2021 Jan 29;22(3):1331. doi: 10.3390/ijms22031331. PMID: 33572752; PMCID: PMC7865937.

[5] Pieroni M, Ciabatti M, Graziani F, Camporeale A, Saletti E, Lillo R, Figliozzi S, Bolognese L. The Heart in Fabry Disease: Mechanisms Beyond Storage and Forthcoming Therapies. Rev Cardiovasc Med. 2022 May 27;23(6):196. doi: 10.31083/j.rcm2306196. PMID: 39077177; PMCID: PMC11273771.

Special Statement: This article is from the MingCeler Biotech WeChat public account. Personal forwarding to Moments is welcome. Media or institutions are prohibited from reprinting to other platforms without authorization. For reprint authorization, please contact us via the public account backend. For other cooperation needs, please contact sales@mingceler.com.

Disclaimer: Some materials are sourced from the internet. If there is any infringement, please contact us for removal. This article is intended for informational purposes only and does not provide treatment recommendations. The views expressed herein do not represent the position of MingCeler Biotech, nor does MingCeler Biotech support or oppose the views expressed.