**Background:** Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficient alpha-galactosidase A (α-Gal A) activity and accumulation of globotriaosylceramide (Gb3) in multiple organs. This results in significant morbidity and mortality, with a 20-year reduction in life expectancy for males and 10-year for females. The review aims to present current and novel therapeutic strategies, including symptomatic and disease-specific treatments.
**Methods:** A systematic literature search was conducted in MEDLINE, Scopus, Embase, Cochrane Library, EudraCT, and ClinicalTrials.gov up to March 21, 2022. Keywords included "Fabry disease" combined with "enzyme replacement therapy", "chaperone treatment", "gene therapy", "substrate reduction therapy", or "mRNA-based therapy". Two independent researchers screened studies, including RCTs, cohort studies, case series, and case reports providing clinical data on FD-specific treatments. Editorials and reviews were also assessed for comprehensiveness.
**Key Results:** The review details clinical manifestations: cardiac involvement in 68% (left ventricular hypertrophy, arrhythmias), renal involvement in 45% (microalbuminuria, progressive failure), peripheral nervous system in 45% (neuropathic pain), eye involvement in 38% (cornea verticillata), central nervous system in 34% (stroke), skin in 34% (angiokeratomas), and ear in 19% (hearing loss). Diagnosis involves α-Gal A activity measurement in males and GLA gene analysis in females, with lyso-Gb3 as a confirmatory biomarker.
Symptomatic treatment is multidisciplinary: for cardiac issues, ACE inhibitors and ARBs are recommended, while amiodarone and beta-blockers are avoided. Renal management includes ACE inhibitors/ARBs targeting protein excretion <500 mg/day, and SGLT2 inhibitors may be beneficial. Neuropathic pain is treated with carbamazepine, gabapentin, or duloxetine. Stroke prevention uses antiplatelets/anticoagulants as indicated.
DISEASE-SPECIFIC TREATMENTS INCLUDE
- **Enzyme Replacement Therapy (ERT):** Agalsidase alfa (0.2 mg/kg biweekly) and agalsidase beta (1.0 mg/kg biweekly) are approved. RCTs showed reduced Gb3 levels, improved neuropathic pain, stabilized renal function, and regression of hypertrophic cardiomyopathy. Neutralizing antibodies occur more with agalsidase beta (83%) than alfa (55%).
- **Chaperone Therapy:** Migalastat (123 mg every other day) is approved for patients with amenable mutations (37-60% of FD patients). The FACETS and ATTRACT trials showed stable renal function, reduced cardiac mass, and comparable outcomes to ERT. Migalastat can cross the blood-brain barrier.
- **Developing Treatments:** Substrate reduction therapies (lucerastat, venglustat) are in phase III trials (MODIFY, CARAT, PERIDOT). Pegunigalsidase alfa (pegylated ERT) showed prolonged stability and reduced immunogenicity in phase 1/2 trials. Moss-aGal (plant-derived ERT) demonstrated safety in a phase 1 trial. Gene therapy includes ex-vivo (lentiviral AVR-RD-01) and in-vivo (adeno-associated virus vectors 4D-310, ST-920, FLT190) approaches, with early data showing near-normal α-Gal A activity and Gb3 reduction. Non-viral nanoparticle-based gene therapy is in animal models.
**Clinical Implications:** Early initiation of FD-specific therapy before irreversible organ damage is critical. The European Fabry Working Group recommends ERT initiation at first signs of kidney, heart, or brain involvement, and may be considered in asymptomatic males ≥16 years. Treatment with agalsidase alfa or beta has shown survival prolongation of >15 years (Fabry Outcome Survey). Migalastat offers an oral alternative for eligible patients. Emerging therapies aim to overcome ERT limitations (infusion burden, antibodies, blood-brain barrier penetration) and may enable more personalized management. A multidisciplinary approach remains essential for comprehensive care.