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 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.

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 Does immunological remission, defined as disappearance of autoantibodies, occur with current treatment strategies? A long-term follow-up study in rheumatoid arthritis patients who achieved sustained DMARD-free status

2019 ◽  
Vol 78 (11) ◽  
pp. 1497-1504 ◽  
Author(s):  
Debbie M Boeters ◽  
Leonie E Burgers ◽  
René EM Toes ◽  
Annette van der Helm-van Mil
Keyword(s):  
Rheumatoid Arthritis ◽  
Treatment Strategies ◽  
Signs And Symptoms ◽  
Current Treatment ◽  
Dmard Therapy ◽  
Before And After ◽  
Long Term Follow Up ◽  
Free Status

ObjectivesSustained disease-modifying antirheumatic drug (DMARD)-free status, the sustained absence of synovitis after cessation of DMARD therapy, is infrequent in autoantibody-positive rheumatoid arthritis (RA), but approximates cure (ie, disappearance of signs and symptoms). It was recently suggested that immunological remission, defined as disappearance of anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF), underlies this outcome. Therefore, this long-term observational study determined if autoantibodies disappear in RA patients who achieved sustained DMARD-free remission.MethodsWe studied 95 ACPA-positive and/or RF-positive RA patients who achieved DMARD-free remission after median 4.8 years and kept this status for the remaining follow-up (median 4.2 years). Additionally, 21 autoantibody-positive RA patients with a late flare, defined as recurrence of clinical synovitis after a DMARD-free status of ≥1 year, and 45 autoantibody-positive RA patients who were unable to stop DMARD therapy (during median 10 years) were studied. Anti-cyclic citrullinated peptide 2 (anti-CCP2) IgG, IgM and RF IgM levels were measured in 587 samples obtained at diagnosis, before and after achieving DMARD-free remission.Results13% of anti-CCP2 IgG-positive RA patients had seroreverted when achieving remission. In RA patients with a flare and persistent disease this was 8% and 6%, respectively (p=0.63). For anti-CCP2 IgM and RF IgM, similar results were observed. Evaluating the estimated slope of serially measured levels revealed that RF levels decreased more in patients with than without remission (p<0.001); the course of anti-CCP2 levels was not different (p=0.66).ConclusionsSustained DMARD-free status in autoantibody-positive RA was not paralleled by an increased frequency of reversion to autoantibody negativity. This form of immunological remission may therefore not be a treatment target in patients with classified RA.

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 Circulating microRNAs in Fabry Disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ke Xiao ◽  
Dongchao Lu ◽  
Jeannine Hoepfner ◽  
Laura Santer ◽  
Shashi Gupta ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Premature Death ◽  
Circulating Mirnas ◽  
Serum Samples ◽  
Significant Differential Expression ◽  
Enzyme Replacement ◽  
Beneficial Effects ◽  
Mirna Sequencing ◽  
Continuous Progress ◽  
Alpha Galactosidase

Abstract Fabry disease is an X-linked deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal). This results in an accumulation of globotriaosylceramide (GL-3/Gb3) in a variety of cells with subsequent functional impairment. The continuous progress of FD often leads to decreased quality of life and premature death caused by multi-organic complications. The overall aim of our study was to determine the amount of circulating miRNAs in Fabry patients and to test whether ERT would alter the level of individual circulating miRNAs. We used miRNA sequencing by the HTG EdgeSeq System to identify the circulating miRNA pool from Fabry patients with and without enzyme replacement therapy (n = 6). In total, 296 miRNAs in serum of patients were identified. Among them 9 miRNAs were further evaluated in extra serum samples (n = 31) using real-time qPCR and 6 of them showed significant differential expression. The resulting miRNA pattern may help to better understand mechanisms involved in the beneficial effects of ERT and these new miRNA markers could help to estimate the efficacy of ERT or to identify Fabry patients with specific need for ERT.

scholarly journals Cell Transplantation Combined with Recombinant Collagen Peptides for the Treatment of Fabry Disease

2020 ◽  
Vol 29 ◽  
pp. 096368972097636
Author(s):  
Daisuke Kami ◽  
Masashi Yamanami ◽  
Takahiro Tsukimura ◽  
Hideki Maeda ◽  
Tadayasu Togawa ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Cell Transplantation ◽  
Financial Burden ◽  
Kidney Injury ◽  
The Body ◽  
Term Survival ◽  
Enzyme Replacement ◽  
Continuous Release ◽  
Alpha Galactosidase

Fabry disease is caused by a decrease in or loss of the activity of alpha-galactosidase, which causes its substrates globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) to accumulate in cells throughout the body. This accumulation results in progressive kidney injury due to glomerulosclerosis and in heart failure due to hypertrophy. Enzyme replacement therapy (ERT) has been used as the standard therapy for Fabry disease, but it causes a significant financial burden, and regular administration is inconvenient for patients. Because of the short half-life of alpha-galactosidase in vivo, therapeutic methods that can supplement or replace ERT are expected to involve continuous release of alpha-galactosidase, even at low doses. Cell transplantation therapy is one of these methods; however, its use has been hindered by the short-term survival of transplanted cells. CellSaic technology, which utilizes cell spheroids that form after cells are seeded simultaneously with a recombinant collagen peptide scaffold called a μ-piece, has been used to improve cell survival upon implantation. In this study, syngeneic murine embryonic fibroblasts were used to generate CellSaic that were transplanted into Fabry mice. These spheroids survived for 28 days in the renal subcapsular space with forming blood vessels. These results indicate CellSaic technology could be a platform to promote cellular graft survival and may facilitate the development of cell transplantation methods for lysosomal diseases.

Conjunctival lymphangiectasia associated with classic Fabry disease

2017 ◽  
Vol 102 (1) ◽  
pp. 54-58 ◽  
Author(s):  
Melanie D Sivley ◽  
Eric L Wallace ◽  
David G Warnock ◽  
William J Benjamin
Keyword(s):  
Fabry Disease ◽  
Dry Eye ◽  
Imaging System ◽  
University Of Alabama ◽  
Multisystem Disease ◽  
Enzyme Replacement ◽  
Clinical Presentations ◽  
Alpha Galactosidase ◽  
The University

BackgroundFabry disease (FD) is a treatable multisystem disease caused by a defect in the alpha-galactosidase gene. Ocular signs of FD, including corneal verticillata, are among the earliest diagnostic findings. Conjunctival lymphangiectasia (CL) has not previously been associated with FD.MethodsWe examined the eyes of a cohort of 13 adult patients, eight men and five women, with documented classic FD, all treated with enzyme replacement therapy (ERT) at the University of Alabama at Birmingham between February 2014 and April 2015. The average age was 48 years with a range of 35–55 years for men and 21–71 years for women. The mean duration of ERT was 8.4 years (men 8.9 years, women 7.6 years) with a range of 4–14 years. Classical Fabry mutations included Q283X, R227X, W236X and W277X. A high resolution Haag-Streit BQ-900 slit lamp with EyeCap imaging system was used to record conjunctival images.ResultsCL was observed in 11 of the 13 patients (85%) despite long-term ERT. Clinical presentations included single cysts, beaded dilatations and areas of conjunctival oedema. Lesions were located within 6 mm of the corneal limbus. Ten of the 13 subjects (77%) had Fabry-related cataracts and all 13 demonstrated bilateral corneal verticillata. Twelve of the 13 patients had evidence of dry eye, 9 of whom were symptomatic, and 10 had peripheral lymphoedema.ConclusionCL represents a common but under-recognised ocular manifestation of FD, which persists despite ERT, and is often accompanied by peripheral lymphoedema and dry eye syndrome.

scholarly journals ANDERSON-FABRY DISEASE: MANIFESTATION AND PROGNOSIS

2017 ◽  
pp. 46-50
Author(s):  
N. O. Pichkur
Keyword(s):  
Fabry Disease ◽  
Activity Level ◽  
Social Adaptation ◽  
Disease Manifestation ◽  
Enzyme Replacement ◽  
Renal Manifestation ◽  
Patient State ◽  
Alpha Galactosidase ◽  
Stage Renal Disease ◽  
End Stage

The aim of the study was to describe diagnostic and treatment experience of Fabry disease in Ukraine, rare inherited multisystem metaboliс disorder with chronic kidney insufficiency as one of signs. The diagnosis was found in nine years old boy with acroparestesia and multiply angiokeratomas after enzymodiagnostic test (determination of lysosomal enzyme alpha-galactosidase A activity level in peripheral blood leucocytes). The parents gave consent to examine of the other child in family, 19 years old boy with myeloradiculonevritis and inferior paraparesis, and glomerulonephritis presented by proteinuria. Fabry disease was confirmed in proband by special enzymodiagnostic test. Clinical-genealogical analysis was exposed by the "phenomenon of grandfather": grandfather exitus from End Stage Renal Disease, probably due renal manifestation of Fabry disease. Enzyme replacement therapy was stabilized patient state, decreased the proteinuria level and saved the renal function. Early and classic signs of Fabry disease which allows to suspect a genetic anomaly were presented in article. Information about Fabry disease physician followed by in-time diagnosis and onset of specific therapy those provide favorable disease course, social adaptation and rehabilitation of patient, effective medical-genetic consultation in gen-compromised families.

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.

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