Cardiac microvascular pathology in Fabry disease: evaluation of endomyocardial biopsies before and after enzyme replacement therapy
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Published on: December 20, 2017
Beth L Thurberg1, John T Fallon, Richard Mitchell
1Department of Pathology, Genzyme Corporation, Cambridge, MA, USA. Beth.Thurberg@genzyme.com
Insights
Recombinant human alpha-galactosidase A effectively clears globotriaosylceramide (GL-3) deposits from heart microvasculature in Fabry disease patients, halting disease progression.
Area of Science:
- Cardiovascular Medicine
- Genetics and Inherited Diseases
- Lysosomal Storage Disorders
Background:
- Fabry disease involves globotriaosylceramide (GL-3) accumulation due to alpha-galactosidase A deficiency.
- Cardiovascular complications like atherosclerosis and hypertrophy occur in Fabry patients.
Purpose of the Study:
- To evaluate the efficacy of recombinant human alpha-galactosidase A in clearing GL-3 deposits in Fabry disease patients.
- To assess the long-term impact of treatment on cardiovascular pathology.
Main Methods:
- Analysis of endomyocardial biopsies from 58 Fabry patients in a Phase 3 trial and open-label extension.
- Comparison of GL-3 levels before and after treatment with recombinant human alpha-galactosidase A versus placebo.
Main Results:
- Five months of treatment achieved complete microvascular GL-3 clearance in 72% of patients, versus 3% for placebo.
- No GL-3 clearance was observed in cardiomyocytes during the initial trial.
- Capillary endothelium remained GL-3 free for up to 60 months in some patients.
Conclusions:
- Long-term recombinant human alpha-galactosidase A treatment may halt vascular pathology progression in Fabry disease.
- This histopathological study provides guidance for clinicians and pathologists managing Fabry patients.
Background:
In classic Fabry patients, accelerated coronary atherosclerosis and left ventricular hypertrophy manifest in the fourth decade; however, signs of cardiovascular disease also are observed later in life in "cardiac variant" patients and symptomatic female heterozygotes. These disturbances are caused by globotriaosylceramide (GL-3) accumulation in the heart resulting from lysosomal alpha-galactosidase A deficiency.
Methods And Results:
We analyzed pretreatment and posttreatment endomyocardial biopsies from 58 Fabry patients enrolled in a 5-month, phase 3, double-blind, randomized, placebo-controlled trial, followed by a 54-month open-label extension study of recombinant human alpha-galactosidase A. Baseline evaluations revealed GL-3 deposits in interstitial capillary endothelial cells and large, laminated inclusions within cardiomyocytes. In this study, we evaluated microvascular GL-3 clearance; no clearance of GL-3 was observed in the cardiomyocytes during this trial. Five months of recombinant human alpha-galactosidase A treatment in the phase 3 trial resulted in complete microvascular clearance of GL-3 from 72% of treated patients compared with only 3% of placebo patients (P<0.001). The placebo group achieved similar results after 6 months of treatment in the open-label trial. In addition, the capillary endothelium remained free of GL-3 for up to 60 months in 6 of 8 patients who consented to an end-of-study biopsy.
Conclusions:
The findings suggest that long-term treatment with recombinant human alpha-galactosidase A may halt the progression of vascular pathology and prevent the clinical manifestations of atherosclerotic disease. This histopathological study should be a useful guide for clinicians and pathologists who diagnose and follow Fabry patients.
