Fabry Disease Therapy: State-of-the-Art and Current Challenges

Azevedo, Olga; Gago, Miguel; Miltenberger-Miltényi, Gábriel; Sousa, Nuno; Cunha, Damião

doi:10.3390/ijms22010206

Cited by 55 publications

(45 citation statements)

References 106 publications

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“…ERT with recombinant α-galactosidase A has been approved for clinical use since 2001. There are two commercially available preparations, agalsidase alfa and agalsidase beta, both administered intravenously every other week at the doses of 0.2 and 1 mg/kg of body weight, respectively [ 175 ].…”

Section: Cardiac Treatment In Fdmentioning

confidence: 99%

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Fabry Disease and the Heart: A Comprehensive Review

Azevedo

Cordeiro

Gago

et al. 2021

IJMS

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Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene that result in a deficiency of the enzymatic activity of α-galactosidase A and consequent accumulation of glycosphingolipids in body fluids and lysosomes of the cells throughout the body. GB3 accumulation occurs in virtually all cardiac cells (cardiomyocytes, conduction system cells, fibroblasts, and endothelial and smooth muscle vascular cells), ultimately leading to ventricular hypertrophy and fibrosis, heart failure, valve disease, angina, dysrhythmias, cardiac conduction abnormalities, and sudden death. Despite available therapies and supportive treatment, cardiac involvement carries a major prognostic impact, representing the main cause of death in FD. In the last years, knowledge has substantially evolved on the pathophysiological mechanisms leading to cardiac damage, the natural history of cardiac manifestations, the late-onset phenotypes with predominant cardiac involvement, the early markers of cardiac damage, the role of multimodality cardiac imaging on the diagnosis, management and follow-up of Fabry patients, and the cardiac efficacy of available therapies. Herein, we provide a comprehensive and integrated review on the cardiac involvement of FD, at the pathophysiological, anatomopathological, laboratory, imaging, and clinical levels, as well as on the diagnosis and management of cardiac manifestations, their supportive treatment, and the cardiac efficacy of specific therapies, such as enzyme replacement therapy and migalastat.

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Section: Cardiac Treatment In Fdmentioning

confidence: 99%

“…Migalastat is a first-in-class pharmacological chaperone therapy for FD, administered orally at the dosage of 123 mg once every other day, which has been approved by the European Medicines Agency for the treatment of FD patients aged ≥ 16 years, with eGFR ≥ 30 mL/min/1.73 m 2 and amenable GLA mutations [ 175 , 196 ].…”

Section: Cardiac Treatment In Fdmentioning

confidence: 99%

Fabry Disease and the Heart: A Comprehensive Review

Azevedo

Cordeiro

Gago

et al. 2021

IJMS

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“…The administration of three doses of the SLN-based vector augmented α-Gal A activity in liver to levels about 10% of that of the wild-type, maybe due to the accumulation of the vector and the subsequent sustained release of the pDNA. Moreover, administration of the SLN-based vector resulted in an increase in α-Gal A activity that reached around 14% and 20% of the wild-type in kidney and heart, respectively; it is important to consider that affectation of these organs is the major cause of morbidity and mortality in Fabry patients [ 38 , 39 , 40 ]. In those tissues, enzyme activity incremented significantly above the naked pDNA after multiple doses.…”

Section: Discussionmentioning

confidence: 99%

“…Brain affectation in FD involves manifestations that can vary in degree and extent, and are mainly characterized by the development of white matter hyperintensities, stroke and ischemia attacks [ 52 ]. Although nanocarriers have been proposed for targeting bioactives to the brain [ 40 ], overcoming the blood–brain barrier (BBB) is still challenging. In our study, we did not detect an increase of α-Gal A activity in brain, neither with the naked pDNA nor with the SLN-based vector.…”

Section: Discussionmentioning

confidence: 99%

α-Galactosidase A Augmentation by Non-Viral Gene Therapy: Evaluation in Fabry Disease Mice

et al. 2021

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Fabry disease (FD) is a monogenic X-linked lysosomal storage disorder caused by a deficiency in the lysosomal enzyme α-Galactosidase A (α-Gal A). It is a good candidate to be treated with gene therapy, in which moderately low levels of enzyme activity should be sufficient for clinical efficacy. In the present work we have evaluated the efficacy of a non-viral vector based on solid lipid nanoparticles (SLN) to increase α-Gal A activity in an FD mouse model after intravenous administration. The SLN-based vector incremented α-Gal A activity to about 10%, 15%, 20% and 14% of the levels of the wild-type in liver, spleen, heart and kidney, respectively. In addition, the SLN-based vector significantly increased α-Gal A activity with respect to the naked pDNA used as a control in plasma, heart and kidney. The administration of a dose per week for three weeks was more effective than a single-dose administration. Administration of the SLN-based vector did not increase liver transaminases, indicative of a lack of toxicity. Additional studies are necessary to optimize the efficacy of the system; however, these results reinforce the potential of lipid-based nanocarriers to treat FD by gene therapy.

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“…Two therapeutic enzymes are available: agalsidase alpha (Replagal®, Takeda); and agalsidase beta (Fabrazyme®, Sanofi). Although significant clinical benefits and a reduction of Gb3 levels in different biofluids and tissues have been reported in patients treated with ERT, the effects are variable depending on the patient gender and age, and on the affected organs [20]. A better understanding of the determinants of an efficient targeting of exogenous enzyme may allow circumventing variable ERT efficacy.…”

Section: Introductionmentioning

confidence: 99%

Autophagy modulation enhances enzyme replacement therapy response in Fabry disease

Abily-Donval

Barbey

Torre

et al. 2021

Preprint

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Fabry disease is a lysosomal disease due to α-galactosidase A (a-GalA) deficiency. Since 2001, Enzyme replacement therapy (ERT) has been used as specific treatment of Fabry disease, with variable effects depending on patient gender and affected organs. In Fabry cells, the endososo-mal/lysosomal system is highly altered. Consequently, the exogenous enzyme may be mistargeted and trapped into intracellular vesicles instead of reaching the lysosomes. In this study, we aimed to investigate the mechanisms underlying the processing of the exogenous enzyme. We used Fabry cells (cultured fibroblasts and podocyte cell line) to study the enzyme internalization and its effects on the catabolism of the main a-Gal A substrate, globotriaosylceramide (Gb3), upon autophagy inhibition. The exogenous enzyme reaches the early endosome in a similar timeframe in Fabry and control cells, while its targeting to lysosomes is delayed in Fabry cells. Gb3 concentration is lowered upon therapeutic enzyme addition or wortmannin treatment with a synergetic effect. These findings illustrate the positive impact of autophagy inhibition on enzyme trafficking and processing, allowing the increase of functional enzyme rate within the lysosome. Given the high cost of ERT, a better understanding of the cellular fate of the exogenous enzyme may lead to improve its targeting to the lysosome.

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Fabry Disease Therapy: State-of-the-Art and Current Challenges

Cited by 55 publications

References 106 publications

Fabry Disease and the Heart: A Comprehensive Review

Fabry Disease and the Heart: A Comprehensive Review

α-Galactosidase A Augmentation by Non-Viral Gene Therapy: Evaluation in Fabry Disease Mice

Autophagy modulation enhances enzyme replacement therapy response in Fabry disease

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