scholarly journals Generation of GLA-Knockout Human Embryonic Stem Cell Lines to Model Autophagic Dysfunction and Exosome Secretion in Fabry Disease-Associated Hypertrophic Cardiomyopathy

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 327 ◽  
Author(s):  
Song ◽  
Chien ◽  
Yarmishyn ◽  
Chou ◽  
Yang ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Fabry Disease ◽  
Disease Model ◽  
Embryonic Stem ◽  
Treatment Strategies ◽  
Autophagic Flux ◽  
Rab Gtpases ◽  
Pharmacological Chaperone ◽  
Enzyme Replacement ◽  
Wide Range

Fabry disease (FD) is a rare inherited disorder characterized by a wide range of systemic symptoms; it is particularly associated with cardiovascular and renal problems. Enzyme replacement therapy and pharmacological chaperone migalastat are the only approved and effective treatment strategies for FD patients. It is well documented that alpha-galactosidase A (GLA) enzyme activity deficiency causes globotriaosylceramide (Gb3) accumulation, which plays a crucial role in the etiology of FD. However, the detailed mechanisms remain unclear, and the lack of a reliable and powerful disease model is an obstacle. In this study, we created such a model by using CRISPR/Cas9-mediated editing of GLA gene to knockout its expression in human embryonic stem cells (hESCs). The cardiomyocytes differentiated from these hESCs (GLA-null CMs) were characterized by the accumulation of Gb3 and significant increases of cell surface area, the landmarks of FD-associated cardiomyopathy. Furthermore, we used mass spectrometry to compare the proteomes of GLA-null CMs and parental wild type CMs and found that the Rab GTPases involved in exocytotic vesicle release were significantly downregulated. This caused impairment of autophagic flux and protein turnover, resulting in an increase of reactive oxygen species and apoptosis. To summarize, we established a FD model which can be used as a promising tool to study human hypertrophic cardiomyopathy in a physiologically and pathologically relevant manner and to develop new therapies by targeting Rab GTPases signaling-related exosomal vesicles transportation.

Treatment of Anderson-Fabry Disease

2020 ◽  
Vol 26 (40) ◽  
pp. 5089-5099 ◽  
Author(s):  
Irene Simonetta ◽  
Antonino Tuttolomondo ◽  
Mario Daidone ◽  
Salvatore Miceli ◽  
Antonio Pinto
Keyword(s):  
Fabry Disease ◽  
Treatment Strategies ◽  
Signs And Symptoms ◽  
Current Treatment ◽  
Viral Gene ◽  
Pharmacological Chaperone ◽  
Enzyme Replacement ◽  
Cell Based Therapy ◽  
Organ Manifestations ◽  
Alpha Galactosidase

: Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, predominantly globotriaosylsphingosine (Gb3) in lysosomes, as well as other cellular compartments of several tissues, causing multi-organ manifestations (acroparesthesias, hypohidrosis, angiokeratomas, signs and symptoms of cardiac, renal, cerebrovascular involvement). Pathogenic mutations lead to a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA). In the presence of high clinical suspicion, a careful physical examination and specific laboratory tests are required. Finally, the diagnosis of Fabry’s disease is confirmed by the demonstration of the absence of or reduced alpha-galactosidase A enzyme activity in hemizygous men and gene typing in heterozygous females. Measurement of the biomarkers Gb3 and Lyso Gb3 in biological specimens may facilitate diagnosis. The current treatment of Anderson-Fabry disease is represented by enzyme replacement therapy (ERT) and oral pharmacological chaperone. Future treatments are based on new strategic approaches such as stem cell-based therapy, pharmacological approaches chaperones, mRNA therapy, and viral gene therapy. : This review outlines the current therapeutic approaches and emerging treatment strategies for Anderson-Fabry disease.

scholarly journals Considerations for Home-Based Treatment of Fabry Disease in Poland during the COVID-19 Pandemic and Beyond

2021 ◽  
Vol 18 (16) ◽  
pp. 8242
Author(s):  
Michał Nowicki ◽  
Stanisława Bazan-Socha ◽  
Mariusz Kłopotowski ◽  
Beata Błażejewska-Hyżorek ◽  
Mariusz Kusztal ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Genetic Diseases ◽  
Healthcare Providers ◽  
Treatment Programs ◽  
Current Therapy ◽  
Term Care ◽  
Pharmacological Chaperone ◽  
Enzyme Replacement ◽  
Home Based ◽  
Rare Genetic Diseases

Current therapy for Anderson–Fabry disease in Poland includes hospital or clinic-based intravenous enzyme replacement therapy with recombinant agalsidase alpha or beta, or oral pharmacological chaperone therapy with migalastat. Some countries around the world offer such treatment to patients in the comfort of their own homes. The 2020–2021 COVID-19 pandemic has pushed global healthcare providers to evolve their services so as to minimize the risk of COVID-19 exposure to both patients and providers; this has led to advances in telemedicine services and the increasing availability of at-home treatment for various procedures including parenteral drug administration. A total of 80% of surveyed Anderson–Fabry disease patients in Poland would prefer home-based treatment, which would be a safe and convenient alternative to clinic-based treatment if patient selection is based on our proposed algorithm. Our recommendations for home-based treatments appear feasible for the long term care of Anderson–Fabry disease patients during the COVID-19 pandemic and beyond. This may also serve as a basis for home-based treatment programs in other rare and ultra-rare genetic diseases.

scholarly journals Switch from enzyme replacement therapy to oral chaperone migalastat for treating fabry disease: real-life data

2020 ◽  
Vol 28 (12) ◽  
pp. 1662-1668 ◽  
Author(s):  
Eleonora Riccio ◽  
◽  
Mario Zanfardino ◽  
Lucia Ferreri ◽  
Ciro Santoro ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Enzyme Replacement Therapy ◽  
Fabry Disease ◽  
Replacement Therapy ◽  
Treatment Options ◽  
Real Life ◽  
Left Ventricular ◽  
Pharmacological Chaperone ◽  
Enzyme Replacement ◽  
Neurologic Function

AbstractThe treatment options for Fabry disease (FD) are enzyme replacement therapy (ERT) with agalsidase alfa or beta, and the oral pharmacological chaperone migalastat. Since few data are available on the effects of switching from ERT to migalastat, we performed a single-center observational study on seven male Fabry patients (18–66 years) to assess the effects of the switch on renal, cardiac, and neurologic function, health status, pain, lyso-Gb3, α-Gal A activity and adverse effects. Data were retrospectively collected at time of diagnosis of FD (baseline, T0), and after 12 months of ERT (T1), and prospectively after 1 year of therapy with migalastat (T2). No patient died or reported renal, cardiac, or cerebrovascular events during the study period. The predefined measures for cardiac, renal and neurologic function, and FD-related symptoms and questionnaires were stable between baseline and the switch, and remained unchanged with migalastat. However, a significant improvement was observed in left ventricular mass index from baseline to T2 (p = 0.016), with a significative difference between the treatments (p = 0.028), and in median proteinuria from T2 vs T1 (p = 0.048). Moreover, scores of the BPI improved from baseline to T1, and remained stable with migalastat. Plasma lyso-Gb3 levels significantly decreased from baseline to T1 (P = 0.007) and T2 (P = 0.003), while did not significantly differ between the two treatments. α-Gal A activity increased from T0 to T2 (p < 0.0001). The frequency of adverse effects under migalastat and ERT was comparable (28% for both drugs). In conclusion, switching from ERT to migalastat is valid, safe and well tolerated.

scholarly journals Fabry Disease

2021 ◽  
Author(s):  
Ida Kåks ◽  
Peter Magnusson
Keyword(s):  
Fabry Disease ◽  
Severe Disease ◽  
Gastrointestinal Symptoms ◽  
Specific Treatment ◽  
Skin Lesions ◽  
Lysosomal Storage ◽  
Pharmacological Chaperone ◽  
Enzyme Replacement ◽  
Related Quality ◽  
Health Related

Fabry disease (FD) is a lysosomal storage disorder where deficient or completely absent activity of the enzyme α-galactosidas A leads to accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in lysosomes. The condition is rare, approximately 1:50,000, although underdiagnosis seems frequent. The condition can affect multiple organ systems, including the skin, nervous system, kidneys, and heart. Early manifestations include skin lesions (angiokeratoma), neuropathic pain, and gastrointestinal symptoms. Later on, FD can result in cardiomyopathy, kidney failure, and stroke. Both lifespan and health-related quality of life are affected negatively by FD. Patients are divided into a classical or a non-classical phenotype based on presentation, where the diagnosis of classical FD requires that a set of specific criteria are met. Patients with non-classical FD often have a less severe disease course, sometimes limited to one organ. The hereditary pattern is X-linked. Thus, men are in general more severely affected than women, although there is an overlap in symptomatic burden. Two types of specific treatment options are available: enzyme replacement therapy and pharmacological chaperone therapy. In addition to this, management of each organ manifestation with usual treatment is indicated.

Rare presentation of Fabry disease as ‘burnt-out’ hypertrophic cardiomyopathy

2021 ◽  
Vol 14 (9) ◽  
pp. e243604
Author(s):  
Sam Williams ◽  
Ahmed El-Medany ◽  
Angus Nightingale ◽  
Yasmin Ismail
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
Fabry Disease ◽  
Left Ventricular ◽  
Diagnostic Tools ◽  
Lysosomal Storage ◽  
Rare Presentation ◽  
Enzyme Replacement ◽  
End Stage Heart Failure ◽  
End Stage

We herein report the case of a 53-year-old man who was historically diagnosed with hypertrophic cardiomyopathy (HCM) and was lost to follow-up, before presenting with end-stage heart failure. This was initially suspected as dilated cardiomyopathy and then ‘burnt-out phase’ of HCM but subsequently the underlying diagnosis was Fabry disease. Fabry disease is an uncommon lysosomal-storage disease due to reduced or absent activity of the alpha-galactosidase A enzyme. Cardiac involvement most frequently comprises left ventricular hypertrophy. Early treatment of the underlying condition with enzyme replacement therapy may prevent the progression to end-stage heart failure. Fabry disease should be considered in all patients presenting with a clinical phenotype of HCM and a historical diagnosis should be re-evaluated in light of new diagnostic tools. Untreated Fabry can progress to a ‘burnt out’ phase, whereby initial hypertrophy undergoes eccentric remodelling to a dilated, severely impaired left ventricle.

scholarly journals Hot topics in Fabry disease

2018 ◽  
Vol 94 (1118) ◽  
pp. 709-713 ◽  
Author(s):  
Tereza Cairns ◽  
Jonas Müntze ◽  
Judith Gernert ◽  
Lisa Spingler ◽  
Peter Nordbeck ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Gene Mutations ◽  
Lysosomal Storage ◽  
Neutralising Antibodies ◽  
Enzyme Replacement ◽  
Clinical Presentations ◽  
Wide Range ◽  
Therapy Effectiveness ◽  
Science Community ◽  
Rare Inborn Error

Fabry disease is a rare inborn error of the enzyme α-galactosidase (α-Gal) and results in lysosomal substrate accumulation in tissues with a wide range of clinical presentations. The disease has attracted a lot of interest over the last years, in particular since enzyme replacement therapy (ERT) has become widely available in 2001. With rising awareness and rising numbers of (diagnosed) patients, physicians encounter new challenges. Over 900 α-Gal gene mutations are currently known, some with doubtful clinical significance, posing diagnostic and prognostic difficulties for the clinician and a lot of uncertainty for patients. Another challenge are patients who develop neutralising antibodies to ERT, which possibly leads to reduced therapy effectiveness. In this article, we summarise the latest developments in the science community regarding diagnostics and management of this rare lysosomal storage disorder and offer an outlook to future treatments.

scholarly journals Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 271
Author(s):  
Ken Kok ◽  
Kimberley C. Zwiers ◽  
Rolf G. Boot ◽  
Hermen S. Overkleeft ◽  
Johannes M. F. G. Aerts ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Molecular Basis ◽  
Diagnostic Procedures ◽  
Neurological Complications ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Pharmacological Chaperone ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Timely Treatment

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by the deficiency of α-galactosidase A (α-GalA) and the consequent accumulation of toxic metabolites such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). Early diagnosis and appropriate timely treatment of FD patients are crucial to prevent tissue damage and organ failure which no treatment can reverse. LSDs might profit from four main therapeutic strategies, but hitherto there is no cure. Among the therapeutic possibilities are intravenous administered enzyme replacement therapy (ERT), oral pharmacological chaperone therapy (PCT) or enzyme stabilizers, substrate reduction therapy (SRT) and the more recent gene/RNA therapy. Unfortunately, FD patients can only benefit from ERT and, since 2016, PCT, both always combined with supportive adjunctive and preventive therapies to clinically manage FD-related chronic renal, cardiac and neurological complications. Gene therapy for FD is currently studied and further strategies such as substrate reduction therapy (SRT) and novel PCTs are under investigation. In this review, we discuss the molecular basis of FD, the pathophysiology and diagnostic procedures, together with the current treatments and potential therapeutic avenues that FD patients could benefit from in the future.

Sign in / Sign up

Export Citation Format

Share Document