A rare disease a day: Fabry disease

Day 5 of ‘a rare disease a day’ following on from Hunter syndrome, Gaucher disease, Tay-Sachs, and Morquio syndrome it is the turn of Fabry disease (which is also  known as Fabry’s disease, Anderson-Fabry disease, angiokeratoma corporis diffusum and alpha-galactosidase A deficiency).

The disease is caused by a deficiency of the enzyme alpha galactosidase A which in turn causes globotriaosylceramide  to accumulate in various tissues and organs which in turn impairs normal functioning. The disease has a whole array of symptoms from pain (neuropathy), renal, cardiac, dermatological and ocular manifestations. Patients have a shortened life span (male life expectancy is 58.2 years) likely due to cardiovascular disease and the need for kidney replacement.

While there is no cure for the disease there is enzyme replacement therapy (ERT) which can improve metabolism, partially prevent disease progression, or reverse some symptoms. The first ERT, Fabrazyme (agalsidase beta, from Genzyme, now part of Sanofi) was approved by FDA in 2003. A second ERT Replagal (agalsidase alpha from Shire) was approved in the EU in 2001. It is not approved in the USA.

As with the other rare diseases described so far, there have been some efforts to find chaperones e.g. galactose,  tuning iminosugars, and others such as1-Deoxy-galactonojirimycin.  Crystal structures of chaperones bound to enzyme are also available. There have also been efforts to understand whether patients with specific mutations will respond to a chaperone. One example is “Fabry_CEP” which provides a database and a predictive tool to evaluate the responsiveness of lysosomal alpha-galactosidase mutants to a small molecule drug, namely 1-Deoxy-galactonojirimycin.

The furthest advanced compound appears to be the Amicus Therapeutics molecule called Migalastat, which was found to be effective in a mouse model of Fabry and was shown to reduce levels of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3) in patients. Migalastat has also been used in phase II clinical trials as a chaperone for the disease. It remains to be seen what percentage of patients with amenable mutations will benefit from this compound, which may suggest that other chaperones will need to be developed. The structure is remarkably similar to miglitol the oral antidiabetic drug, which makes you wonder if it was ever tested in vitro as a chaperone for Fabry or other similar diseasesmigalastat and miglitol.


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