Fabry disease is a progressive and multisystemic condition, for which a multidisciplinary approach to treatment is recommended.1,2 The long-term management of patients with Fabry disease includes timely treatment of symptoms and regular assessment of disease progression.2 Disease-specific therapies, if indicated, may be combined with symptomatic treatments to manage the complications associated with Fabry disease. Fabry disease can affect patients both emotionally and physically, as well as their families.2 Therefore, support and counselling is recommended throughout the process of diagnosis, investigation and therapy for patients and their families.3 Genetic counselling may also be offered to patients with Fabry disease and their families in order to understand the genetic inheritance of the disease and to identify at-risk family members.2,4
At present, there are two intravenous enzyme replacement therapies available for the treatment of Fabry disease: agalsidase alfa and agalsidase beta.5,6 In patients with Fabry disease, deficient enzymatic activity of alpha-galactosidase A (α-Gal A) leads to an accumulation of the glycosphingolipids globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) within almost all cell types and various organs.7-9 Enzyme replacement therapy introduces recombinant enzyme α-Gal A into lysosomes to help address the underlying enzyme deficiency and restore breakdown of accumulated Gb3 in patients with Fabry disease.10 Additionally, one oral chaperone therapy, migalastat, is available for patients diagnosed with Fabry disease and who have an amenable variant.11 In some patients with Fabry disease, α-Gal A may be improperly folded due to missense variants in the GLA gene.12,13 Misfolded α-Gal A variants have residual enzymatic activity but are considered unstable.14 A pharmacological chaperone can bind to α-Gal A to stabilise its structure in the endoplasmic reticulum, thereby allowing proper trafficking of Gb3 to the lysosomes for processing.15-17 The availability of treatments differs between countries. For further information, please consult your local prescribing information.
What future treatments could be available for Fabry disease?
The first available therapeutic option for patients with Fabry disease was enzyme replacement therapy, followed by chaperone therapy. Current and investigational therapies for Fabry disease are outlined in Figure 1.7 Potential future therapeutic modalities for Fabry disease could include alternative enzyme replacement therapies, substrate reduction therapy and gene therapy. Substrate reduction therapies function as a glucosylceramide synthase inhibitor to prevent the accumulation of Gb3 via a reduction in the conversion of ceramide to glycosphingolipid.7,18 The potential advantages of a small-molecule substrate reduction therapy include its oral route of administration and that it may be indicated for all patients with Fabry disease, regardless of genotype.18 Both ex vivo and in vivo gene therapy are also being investigated for Fabry disease. Using an ex vivo approach, haematopoietic stem cells are harvested from a patient with Fabry disease. Following gene editing, the patient’s haematopoietic stem cells are infused back into the patient for engraftment after administration of myeloablative therapy. Using in vivo gene therapy, a vector with gene editing is inserted directly into the patient with Fabry disease. Consequently, the cells of the patient directly undergo gene editing to correct the deficient protein. An additional investigational therapeutic modality for Fabry disease is the administration of α-Gal A mRNA to facilitate production of α-Gal A, independent of the need for myeloablative therapy or the insertion of viral vectors for gene transduction.7
Current and potential future therapies for Fabry disease. Reproduced and adapted with permission from Felis A et al. Kidney Int Rep 2019; 5: 407-413.7
C-ANPROM/INT/FAB/0017; Date of preparation: March 2021
- Vardarli I, Rischpler C, Herrmann K, et al. Diagnosis and screening of patients with Fabry disease. Ther Clin Risk Manag 2020; 16: 551-558.
- Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab 2018; 123: 416-427.
- Hughes DA, Evans S, Milligan A, et al. A multidisciplinary approach to the care of patients with Fabry disease. In: Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, UK: Oxford PharmaGenesis, 2006.
- Laney DA, Bennett RL, Clarke V, et al. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns 2013; 22: 555-564.
- Sanofi Genzyme. Fabrazyme® EU Summary of Product Characteristics. Last updated November 2020.
- Shire Pharmaceuticals Ltd. Replagal® EU Summary of Product Characteristics. Last updated November 2020.
- Felis A, Whitlow M, Kraus A, et al. Current and investigational therapeutics for Fabry disease. Kidney Int Rep 2019; 5: 407-413.
- Schiffmann R, Hughes DA, Linthorst GE, et al. Screening, diagnosis, and management of patients with Fabry disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 2017; 91: 284-293.
- Brady RO, Gal AE, Bradley RM, et al. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967; 276: 1163-1167.
- El Dib R, Gomaa H, Carvalho RP, et al. Enzyme replacement therapy for Anderson-Fabry disease. Cochrane Database Syst Rev 2016; 7: CD006663.
- Amicus Therapeutics Europe Ltd. Galafold® EU Summary of Product Characteristics. Last updated August 2020.
- Garman SC, Garboczi DN. Structural basis of Fabry disease. Mol Genet Metab 2002; 77: 3-11.
- Garman SC, Garboczi DN. The molecular defect leading to Fabry disease: structure of human alpha-galactosidase. J Mol Biol 2004; 337: 319-335.
- Yam GH-F, Bosshard N, Zuber C, et al. Pharmacological chaperone corrects lysosomal storage in Fabry disease caused by trafficking-incompetent variants. Am J Physiol Cell Physiol 2006; 290: C1076-C1082.
- McCafferty EH, Scott LJ. Migalastat: a review in Fabry disease. Drugs 2019; 79: 543-554.
- Fan JQ, Ishii S, Asano N, et al. Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med 1999; 5: 112-115.
- Yam GH-F, Zuber C, Roth J. A synthetic chaperone corrects the trafficking defect and disease phenotype in a protein misfolding disorder. FASEB J 2005; 19: 12-18.
- Welford RWD, Mühlemann A, Garzotti M, et al. Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types. Hum Mol Gen 2018; 27: 3392-3403.