Chaperone Therapy in Fabry Disease

Fabry disease is a rare genetic disorder that causes severe and irreversible organ damage due to the buildup of a fatty substance called globotriaosylceramide (Gb3 or GL-3) inside cells. This accumulation is caused by a deficiency of an enzyme called alpha-galactosidase A. Chaperone therapy can help cells digest Gb3.

How chaperone therapy works in Fabry disease

Cells have a tight quality-control mechanism that ensures imperfect proteins do not get out of a compartment called the endoplasmic reticulum. This is where proteins are synthesized inside the cells and sent out to their destinations, or rapidly destroyed if faulty.

In Fabry disease, because of mutations in the GLA gene, different versions of the alpha-galactosidase A enzyme that have very little or no activity are produced. Alpha-galactosidase A is the enzyme responsible for Gb3 digestion inside lysosomes, another cellular compartment that disposes of waste in the cell. Because of the quality-control mechanism, mutated forms of alpha-galactosidase A are never delivered to the lysosomes even though they may perform their functions to some extent.

Chaperones are small molecules that assist proteins in becoming functional by helping them take the correct shape and stay stable. With chaperone therapy, some faulty forms of alpha-galactosidase A can be corrected and delivered to the lysosomes so that the excess Gb3 can be broken down.

Galafold for the treatment of Fabry disease

Galafold (migalastat), developed by Amicus Therapeutics, is the first oral chaperone therapy for Fabry disease.

More than 700 mutations have been associated with faulty alpha-galactosidase A formation, causing Fabry disease. Galafold can restore the activity of 269 of these faulty forms of the enzyme.

The U.S. Food and Drug Administration approved Galafold in August 2018 under the accelerated approval program, which is for medications that fill an unmet medical need and are likely to benefit patients but require further studies to confirm their potential. The medication was also granted priority review and orphan drug designation.

Galafold is also approved in Australia, Canada, the European Union, Israel, South Korea, and Japan to treat Fabry patients over 16 years of age.


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