Strong increase of leukocyte apha‐galactosidase A activity in two male patients with Fabry disease following oral chaperone therapy

Abstract

Background Fabry disease (OMIM 301500) is an X‐linked disorder caused by alpha‐galactosidase A (α‐Gal A) deficiency. The administration of a pharmacologic chaperone (migalastat) in Fabry patients with amenable mutations has been reported to improve or stabilize organ damages and reduce lyso‐Gb3 plasma level. An increase of α‐Gal A activity has been observed in vitro in cells expressing amenable GLA mutations when incubated with migalastat. The impact of the drug on α‐Gal A in vivo activity has been poorly studied. Methods We conducted a retrospective analysis of two unrelated male Fabry patients with p.Asn215Ser (p.N215S) variant. Results We report the important increase of α‐Gal A activity in blood leukocytes reaching normal ranges of activity after about 1 year of treatment with migalastat. Cardiac parameters improved or stabilized with the treatment. Conclusion We confirm in vivo the effects of migalastat that have been observed in N215S carriers in vitro. The increase of α‐Gal A activity may be the strongest marker for biochemical efficacy. The normalization of enzyme activity could become the new therapeutic target to achieve.

Therapeutic Role of Pharmacological Chaperones in Lysosomal Storage Disorders: A Review of the Evidence and Informed Approach to Reclassification

“…The split between preclinical and clinical studies was equal. A summary of the included clinical studies for Fabry disease is shown in Table 2 [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 43 , 44 , 45 ]. A summary of the preclinical studies is shown in the Supplementary Material (Table S2) [ 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ].…”

Molecular mechanisms in chaperonopathies: clues to understanding the histopathological abnormalities and developing novel therapies

“…In this regard, current research aims at finding and standardizing compounds and delivery means targeting as specifically as possible the pathogenic chaperone [82][83][84][85][86]. If the chaperonopathy is by defect, positive chaperonotherapy is indicated, consisting in chaperone gene or protein replacement, or the use of manufactured chaperoning structures [87][88][89]; or chaperone-protein functional boosting with chemical compounds, namely chemical chaperones similar to those utilized for restoring enzymatic activity in genetic enzymopathies [82,[90][91][92][93]. Other approaches include the use of harmless stressors to induce production of a chaperone responsive to them when it is below the physiological concentration; namely, in cases of chaperonopathy by defect of the quantitative type [94].…”