Fabry disease is a rare genetic disorder that causes severe and irreversible organ damage because of a fatty substance called globotriaosylceramide (Gb3 or GL-3) that builds up inside cells due to the deficiency of an enzyme called alpha-galactosidase A. Chaperone therapy is a new investigational method to help cells digest Gb3.
How chaperone therapy works in Fabry disease
Cells have a tight quality control mechanism that ensures imperfect proteins cannot get out of a compartment called the endoplasmic reticulum, which 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 in 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.
Migalastat for Fabry treatment
More than 700 mutations have been associated with faulty alpha-galactosidase A formation, causing Fabry disease. Migalastat can restore the activity of 313 of these mutated alpha-galactosidase A versions.
Migalastat is currently approved in Australia, Canada, the European Union, Israel, South Korea, and Japan to treat Fabry patients older than 16. Although it is not yet approved in the U.S. the U.S. Food and Drug Administration (FDA) recently granted migalastat fast track designation, and the company’s new drug application is currently under priority review.
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