[Chaperone molecules: The example of Fabry disease]

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Fabry disease results from GLA gene mutations, leading to alpha-galactosidase A (α-gal A) deficiency and substrate accumulation.
• Current treatments include enzyme replacement therapy, but a novel approach is needed.

Purpose of the Study:

• To evaluate the efficacy and safety of migalastat, a pharmacological chaperone, as a treatment for Fabry disease.
• To compare migalastat with placebo and enzyme replacement therapy in clinical trials.

Main Methods:

• Phase III clinical trials (FACETS and ATTRACT) were conducted.
• Migalastat's in vivo effects were analyzed in patients with GLA gene mutations sensitive to the drug.
• Pharmacogenetic testing identified eligible patients (approx. 35% of mutations).

Main Results:

• Migalastat demonstrated promising results in reducing left ventricular mass index in patients with cardiac hypertrophy compared to enzyme replacement therapy.
• Renal effects of migalastat were comparable to enzyme replacement therapy.
• The treatment targets specific GLA gene mutations, offering a personalized approach.

Conclusions:

• Migalastat represents a novel oral, personalized therapy for Fabry disease, targeting specific genetic mutations.
• It shows potential as an effective alternative to enzyme replacement therapy, particularly for cardiac manifestations.
• This marks a new era in managing conformational diseases like Fabry disease.