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1.
Rev Prat ; 70(5): 537-540, 2020 May.
Artículo en Francés | MEDLINE | ID: mdl-33058644

RESUMEN

Fabry disease. Fabry disease is an X-linked disorder in which lysosomal alpha-galactosidase A is lacking, leading to enzyme-substrate accumulation and tissues dysfunction. Acroparesthesia, angiokeratoma, familial nephropathy or hypertrophic cardiomyopathy should suggest Fabry disease. Enzymatic assay allows diagnosis in men but genetic assay is needed for women. Enzyme replacement therapy is available since 2001 and a pharmacologic chaperone since 2016.


Asunto(s)
Enfermedad de Fabry , Nefritis Hereditaria , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/genética , Enfermedad de Fabry/terapia , Femenino , Humanos , Masculino , alfa-Galactosidasa/genética , alfa-Galactosidasa/uso terapéutico
2.
Brasília; CONITEC; out. 2020.
No convencional en Portugués | BRISA/RedTESA | ID: biblio-1141493

RESUMEN

CONTEXTO: Doença de Fabry (DF) é uma condição genética rara em que a ausência ou atividade reduzida da enzima αgalactosidase A (αGal-A) provoca acúmulo do seu substrato, globotriaosilceramida (Gb3), nas células do organismo, afetando principalmente os sistemas nervoso, renal e cardíaco. Pacientes com DF, em especial homens com o tipo clássico, apresentam impacto negativo em qualidade e expectativa de vida. O SUS oferece tratamento sintomático e paliativo para a DF. Há disponíveis comercialmente terapias específicas para a doença, como terapia de reposição enzimática (TRE) (alfa e beta-agalsidase) e chaperonas (migalastate). TECNOLOGIA: Alfagalsidase (Replagal®) 0,2mg/kg intravenosa a cada duas semanas e Beta-agalsidase (Fabrazyme®) 1mg/kg intravenosa a cada duas semanas. PERGUNTA: O uso da alfagalsidase ou beta-agalsidase é eficaz, seguro e custo-efetivo em pacientes com doença de Fabry? EVIDÊNCIAS CIENTÍFICAS: A melhor evidência de eficácia da alfagalsidase é baseada em dois ensaios clínicos randomizados, controlados por placebo e inclusão de 41 pacientes adultos do sexo masculino e fenótipo clássico da DF, acompanhados por 6 meses. Foi observada redução significativa dos níveis de dor, massa ventricular esquerda e concentração plasmática de Gb3 (certeza moderada da evidência). Não foram localizados estudos comparativos com pacientes pediátricos ou adultos do sexo feminino com DF tratados com alfagalsidase. A melhor evidência de eficácia da beta-agalsidase é baseada em dois ensaios clínicos randomizados, controlados por placebo e inclusão de 140 pacientes com idade superior a 16 anos, de ambos os sexos, e acompanhamento por até 35 meses. Não foram identificados benefícios nos desfechos de qualidade de vida, dor e desfechos composto incluindo função renal, doenças cardíacas e doenças cerebrovasculares em análise por intenção de tratar (certeza moderada da evidência). Foi observada redução significativa da concentração plasmática de Gb3 (certeza moderada da evidência). Ambas as enzimas apresentaram perfil de segurança semelhante a placebo (certeza moderada da evidência). AVALIAÇÃO ECONÔMICA: Os dois demandantes apresentaram avaliações de custo-utilidade distintas, mas ambas baseadas em modelos de Markov já publicados e utilizando os mesmos parâmetros de efetividade, utilidade e utilização de recursos dos estudos internacionais originais. Com custo unitário proposto de R$3.802,22 (ICMS 18%) e custo anual por paciente de R$395.430,88, o demandante da alfagalsidase estimou que o tratamento representaria ganho de 14,74 anos de vida ajustados pela qualidade (QALY) em horizonte lifetime e custo incremental de R$5.684.051, composto quase inteiramente pelo custo do medicamento. A razão de custo efetividade incremental (RCEI) foi estimada em R$385.689/QALY. O demandante da beta-agalsidase apresentou proposta de preço de R$7.275,86 por frasco (ICMS 18%), com custo anual por paciente de R$378.344,72. Foi estimado ganho de 1,43 QALY e custo incremental de R$6.706.163, resultando numa RCEI de R$4.699.570/QALY. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O demandante da alfagalsidase estimou um impacto orçamentário incremental de cerca de R$250 milhões ao ano para atender aproximadamente 500 pacientes com fenótipo clássico da DF, resultando em R$1,3 bilhão acumulado em 5 anos. Para a beta-agalsidase, o demandante estimou impacto orçamentário incremental de cerca de R$230 milhões ao ano para atender em torno de 600 pacientes adultos com DF, com impacto total de R$1,1 bilhão em 5 anos. Como cenário alternativo, propõe-se uma estimativa de impacto orçamentário incluindo todos os pacientes com DF (cerca de 1.000 ao ano), distribuídos equitativamente entre as duas enzimas. O impacto orçamentário proposto resultou em cerca de R$380 milhões ao ano e R$1,9 bilhão acumulado em 5 anos. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificadas três tecnologias para o tratamento de pacientes adultos de ambos os sexos com doença de Fabry: lucerastate alfa (oral) e pegnigalsidase alfa (intravenosa), ambas sem registros na Anvisa, FDA ou EMA; e migalastate (oral), com registro nas três agências. Para a população pediátrica, foram identificados estudos fase 3 em andamento com migalastate e com beta-agalsidase. CONSIDERAÇÕES FINAIS: O benefício da alfagalsidase ou beta-agalsidase para DF foi observado apenas em desfechos pouco importantes para a tomada de decisão, sem evidências de modificação no curso natural da doença. O impacto orçamentário ao SUS é potencialmente superior à sua capacidade de pagamento. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O Plenário da Conitec considerou que as melhores evidências científicas disponíveis são limitadas em número de pacientes incluídos e tempo de acompanhamento, e não demonstram benefício em desfechos clínicos importantes ou modificação do curso natural da doença. Soma-se a isso o grande impacto orçamentário que a incorporação representaria ao SUS. Assim, a Conitec, em sua 89ª reunião ordinária, realizada no dia 05 de agosto de 2020, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar não favorável à incorporação no SUS do medicamento alfagalsidase para pacientes acima de sete anos com diagnóstico confirmado de doença de Fabry e do medicamento beta-agalsidase para pacientes acima de 16 anos com diagnóstico confirmado de Doença de Fabry. CONSULTA PÚBLICA: A consulta pública ficou vigente no período entre 24 de agosto e 14 de setembro de 2020. Foram recebidas 1.939 contribuições, sendo 90 por meio do formulário técnico-científico e 1.849 por meio do formulário de experiência ou opinião. As contribuições versaram principalmente sobre: 1) inclusão de estudos com menor qualidade metodológica diante da raridade da doença; 2) indicação de uma subpopulação de pacientes para os quais a TRE seria indicada; 3) inconsistência com recomendações anteriores da Conitec para outras doenças raras; 4) necessidade de avaliação do medicamento migalastate; 5) relatos de experiência com as enzimas, indicando melhora especialmente em qualidade de vida, incluindo componentes físicos e emocionais. O Plenário da Conitec considerou, entretanto, que as evidências científicas disponíveis não comprovam uma interrupção da progressão da doença de Fabry pelas enzimas analisadas e entendeu que não houve argumentação suficiente para alterar a recomendação inicial. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da Conitec presentes na 91ª reunião ordinária, no dia 08 de outubro de 2020, deliberaram por unanimidade recomendar a não incorporação no SUS do medicamento alfagalsidase para terapia crônica de reposição enzimática em pacientes acima de 7 anos com diagnóstico confirmado de doença de Fabry e do medicamento beta-agalsidase para tratamento de longo prazo da reposição enzimática em pacientes acima de 16 anos com diagnóstico confirmado de Doença de Fabry, devido a: 1) não comprovação de interrupção da progressão da doença, 2) evidências limitadas quanto ao número de pacientes incluídos nos estudos clínicos comparativos, 3) evidências limitadas quanto ao tempo de acompanhamento dos pacientes nos estudos comparativos, 4) elevado impacto orçamentário que a incorporação representaria ao SUS. Foram assinados os Registros de Deliberação nº 568/2020 e 569/2020, respectivamente. DECISÃO: Não incorporar a alfagalsidase e a beta-agalsidase para o tratamento da doença de Fabry, no âmbito do Sistema Único de Saúde - SUS, conforme Portaria nº 56, publicada no Diário Oficial da União nº 224, seção 1, página 65, em 24 de novembro de 2020.


Asunto(s)
Humanos , Enfermedad de Fabry/tratamiento farmacológico , beta-Galactosidasa/uso terapéutico , alfa-Galactosidasa/uso terapéutico , Evaluación de la Tecnología Biomédica , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economía
3.
Intern Med ; 59(7): 971-976, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32238663

RESUMEN

Mulberry cells are often present in the urinary sediments of patients with Fabry disease (FD). We herein report two patients with FD undergoing enzyme replacement therapy (ERT). A 41-year-old man was diagnosed based on lack of α-galactosidase A activity. ERT was subsequently administered. A 40-year-old woman was diagnosed based on urinary Mulberry cells and genetic testing, and ERT was initiated. While the renal function of the male patient deteriorated, the Mulberry cells disappeared in the female patient after ERT was administered. The detection of urinary Mulberry cells can contribute to the diagnosis as well as serve as a biomarker for the response to treatment.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Podocitos/patología , Orina/citología , Adulto , Biomarcadores , Enfermedad de Fabry/genética , Enfermedad de Fabry/patología , Femenino , Pruebas Genéticas , Humanos , Masculino , Microscopía Electrónica , Podocitos/ultraestructura , alfa-Galactosidasa/metabolismo , alfa-Galactosidasa/uso terapéutico
4.
Mol Genet Metab ; 129(2): 142-149, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31879214

RESUMEN

BACKGROUND: Two established scores, the Mainz Severity Score Index (MSSI) and Fabry Disease Severity Scoring System (DS3), quantify the disease burden in Fabry disease (FD), while the recent developed FAbry STabilization indEX (FASTEX) aims to detect disease progression. OBJECTIVE: MSSI, DS3 and FASTEX were compared to evaluate disease stability or progression in a prospective cohort of Fabry patients under enzyme replacement therapy (ERT). METHODS: Disease load of 62 patients (28 [45%] females) treated with ERT (26 [42%] under agalsidase-alfa) was assessed using the current scores and re-assessed after 12 months of treatment. Fifteen (24%) patients were ERT-naïve at baseline. RESULTS: All scores showed a correlation with each other, while MSSI and DS3 showed the strongest (Pearson r: 0.81, p < .0001). Plasma lyso-Gb3 levels in naïve patients correlated with increasing DS3 and MSSI scores (Pearson r: 0.60, p < .05; Pearson r: 0.64, p < .01; respectively), but not with the total weighted FASTEX score. Longitudinal analysis suggested a stable disease course using DS3 and MSSI. Only males long-term-treated with agalsidase-alfa presented with a slight increase of the general MSSI score (p = .0084). By contrast, the FASTEX score demonstrates that only 21 patients (33.9%) were stable, all other patients presented a disease progression. Patients with an unstable FASTEX mainly suffered from a significant loss of renal function (eGFRcreat: -2.7 ± 7.3 ml/min/1.73 m2, p = .0298). CONCLUSION: We conclude that the FASTEX seems to be a simple and user friendly, valuable tool to assess early changes in disease progression even in smaller patient cohorts and short term surveillance.


Asunto(s)
Costo de Enfermedad , Enfermedad de Fabry/diagnóstico , Índice de Severidad de la Enfermedad , Adulto , Anciano , Progresión de la Enfermedad , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/patología , Femenino , Humanos , Isoenzimas/uso terapéutico , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , alfa-Galactosidasa/uso terapéutico
5.
Circ Cardiovasc Imaging ; 12(12): e009430, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31826677

RESUMEN

BACKGROUND: Cardiac response to enzyme replacement therapy (ERT) in Fabry disease is typically assessed by measuring left ventricular mass index using echocardiography or cardiovascular magnetic resonance, but neither quantifies myocardial biology. Low native T1 in Fabry disease represents sphingolipid accumulation; late gadolinium enhancement with high T2 and troponin elevation reflects inflammation. We evaluated the effect of ERT on myocardial storage, inflammation, and hypertrophy. METHODS: Twenty patients starting ERT (60% left ventricular hypertrophy-positive) were compared with 18 patients with early disease and 18 with advanced disease over 1 year at 3 centers. Cardiovascular magnetic resonance (left ventricular mass index, T1, T2, global longitudinal strain, and late gadolinium enhancement) and biomarkers (high-sensitive troponin-T and NT-proBNP [N-terminal Pro-B-type natriuretic peptide]) at baseline (pre-ERT) and 12 months were performed. Early disease controls were stable, treatment-naïve patients (mainly left ventricular hypertrophy-negative); advanced disease controls were stable, established ERT patients (mainly left ventricular hypertrophy-positive). RESULTS: Over 1 year, early disease controls increased maximum wall thickness and left ventricular mass index (9.8±2.7 versus 10.2±2.6 mm; P=0.010; 65±15 versus 67±16 g/m2; P=0.005) and native T1 fell (981±58 versus 959±61 ms; P=0.002). Advanced disease controls increased T2 in the late gadolinium enhancement area (57±6 versus 60±7 ms; P=0.023) with worsening global longitudinal strain (-13.2±3.4 versus -12.1±4.8; P=0.039). Newly treated patients had a small reduction in maximum wall thickness (14.8±5.9 versus 14.4±5.7 mm; P=0.028), stable left ventricular mass index (93±42 versus 92±40 g/m2; P=0.186) and a reduction in T1 lowering (917±49 versus 931±54 ms; P=0.017). CONCLUSIONS: Fabry myocardial phenotype development is different at different disease stages. After 1 year of ERT initiation, left ventricular hypertrophy-positive patients have a detectable, small reduction in left ventricular mass and storage.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Isoenzimas/uso terapéutico , Miocardio/metabolismo , Proteínas Recombinantes/uso terapéutico , Esfingolípidos/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , alfa-Galactosidasa/uso terapéutico , Adulto , Anciano , Progresión de la Enfermedad , Enfermedad de Fabry/diagnóstico por imagen , Enfermedad de Fabry/enzimología , Enfermedad de Fabry/fisiopatología , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/enzimología , Hipertrofia Ventricular Izquierda/fisiopatología , Londres , Imagen por Resonancia Magnética , Persona de Mediana Edad , Miocardio/patología , Nueva Gales del Sur , Fenotipo , Estudios Prospectivos , Recuperación de la Función , Factores de Tiempo , Resultado del Tratamiento
6.
Sci Rep ; 9(1): 15277, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31649303

RESUMEN

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.


Asunto(s)
MicroARN Circulante/sangre , Terapia de Reemplazo Enzimático/métodos , Enfermedad de Fabry/sangre , alfa-Galactosidasa/uso terapéutico , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven
7.
G Ital Nefrol ; 36(4)2019 Jul 24.
Artículo en Italiano | MEDLINE | ID: mdl-31373466

RESUMEN

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 and several issues has been discovered up to now leading to increasing knowledge and awareness of the disease. However, several aspects are still unclear and under investigation. Thus, the new challenges that physicians encounter are the discovering of the pathogenic mechanisms, the neutralising antibodies to ERT, the long-term efficacy of therapies. In this article, we summarise and review the latest developments in the science community regarding diagnosis, management and monitoring of Fabry disease concerning in particular its physiopathology, novel biomarkers, antibodies development and novel treatment options.


Asunto(s)
Enfermedad de Fabry/complicaciones , Enfermedades Renales/etiología , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapéutico , Progresión de la Enfermedad , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/genética , Femenino , Glomeruloesclerosis Focal y Segmentaria/etiología , Glucolípidos/metabolismo , Heterocigoto , Humanos , Isoenzimas/inmunología , Isoenzimas/uso terapéutico , Enfermedades Renales/diagnóstico , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , Masculino , Estrés Oxidativo , Podocitos/metabolismo , Podocitos/patología , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéutico , Factores Sexuales , Esfingolípidos/metabolismo , Trihexosilceramidas/metabolismo , alfa-Galactosidasa/inmunología , alfa-Galactosidasa/uso terapéutico
8.
Transplant Proc ; 51(9): 3171-3173, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31371217

RESUMEN

Fabry's disease is a X-linked hereditary disease that causes the accumulation of glycosphingolipids in tissues and organs, including the kidneys and heart. This can result in both chronic kidney disease and cardiac dysfunction, including arrhythmias and heart failure. We describe a case of a 62-year-old male with Fabry's disease undergoing successful combined heart and kidney transplantation for chronic renal failure and low-output systolic heart failure. The patient has normal cardiac function and normal renal function 7 years after transplantation, while being maintained on enzyme replacement therapy with recombinant human alpha-galactosidase A. Fabry's disease is not a contraindication for organ transplantation, even in patients presenting with both renal failure and heart failure.


Asunto(s)
Enfermedad de Fabry/complicaciones , Insuficiencia Cardíaca/cirugía , Trasplante de Corazón/métodos , Fallo Renal Crónico/cirugía , Trasplante de Riñón/métodos , Enfermedad de Fabry/tratamiento farmacológico , Insuficiencia Cardíaca/genética , Humanos , Fallo Renal Crónico/genética , Masculino , Persona de Mediana Edad , alfa-Galactosidasa/uso terapéutico
9.
Adv Ther ; 36(10): 2866-2880, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31435831

RESUMEN

INTRODUCTION: Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A. Symptoms include neuropathic pain and gastrointestinal problems, such as diarrhoea. To inform and support the design of a Phase III clinical trial for a new oral treatment for Fabry disease, this study evaluated patients' experiences of Fabry disease symptoms, the impact of symptoms on their quality of life, and their views on participating in clinical trials. METHODS: An online survey questionnaire was distributed to patients with Fabry disease, through relevant patient organisations. The questionnaire consisted mainly of quantitative, closed questions with pre-defined response options. Fabry-specific pain intensity and its impact on quality of life were rated on a scale from 0 to 10. RESULTS: In total, 367 patients completed the survey, of whom half reported frequent pain, moderate to severe pain, and pain in their hands and feet. Pain frequency, intensity and location were similar for males and females. There was no clear association between Fabry-specific pain and the use of enzyme replacement therapy (ERT), with moderate to severe pain reported by 80.4% of participants receiving ERT and by 75.0% of participants not receiving ERT. Of participants who were receiving ERT, 35.7% said they were willing to discontinue it to take part in a clinical trial testing a new oral drug for treating Fabry disease. Gastrointestinal symptoms were more heterogeneous in nature and frequency than Fabry-specific pain, but still affected a significant proportion of participants. CONCLUSIONS: Both male and female patients with Fabry disease experience significant Fabry-specific pain, which affects their quality of life. Furthermore, frequent diarrhoea affects many patients. The symptoms occur independently of the use of ERT. This suggests the healthcare needs of patients with Fabry disease are not being fully met, and additional treatments are required to improve symptoms and quality of life. FUNDING: This study was sponsored by Actelion Pharmaceuticals Ltd. Study sponsorship was transferred to Idorsia Pharmaceuticals Ltd in July 2018.


Asunto(s)
Terapia de Reemplazo Enzimático/métodos , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/psicología , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/psicología , Calidad de Vida/psicología , alfa-Galactosidasa/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios
10.
Nat Commun ; 10(1): 1785, 2019 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-31040271

RESUMEN

Lysosomal replacement enzymes are essential therapeutic options for rare congenital lysosomal enzyme deficiencies, but enzymes in clinical use are only partially effective due to short circulatory half-life and inefficient biodistribution. Replacement enzymes are primarily taken up by cell surface glycan receptors, and glycan structures influence uptake, biodistribution, and circulation time. It has not been possible to design and systematically study effects of different glycan features. Here we present a comprehensive gene engineering screen in Chinese hamster ovary cells that enables production of lysosomal enzymes with N-glycans custom designed to affect key glycan features guiding cellular uptake and circulation. We demonstrate distinct circulation time and organ distribution of selected glycoforms of α-galactosidase A in a Fabry disease mouse model, and find that an α2-3 sialylated glycoform designed to eliminate uptake by the mannose 6-phosphate and mannose receptors exhibits improved circulation time and targeting to hard-to-reach organs such as heart. The developed design matrix and engineered CHO cell lines enables systematic studies towards improving enzyme replacement therapeutics.


Asunto(s)
Lisosomas/enzimología , Animales , Células CHO , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/enzimología , Enfermedad de Fabry/metabolismo , Glicosilación , Masculino , Ratones , Ratones Noqueados , Proteínas Recombinantes/uso terapéutico , alfa-Galactosidasa/uso terapéutico
11.
Cell Physiol Biochem ; 52(5): 1139-1150, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30990584

RESUMEN

BACKGROUND/AIMS: Fabry disease (FD) is a lysosomal storage disorder characterized by impaired alpha-galactosidase A (α-Gal A) enzyme activity due to mutations in the GLA gene. While virtually all tissues are affected, renal damage is particularly critical for the patients' outcome. Currently, powerful diagnostic tools and in vivo research models to study FD in the kidney are lacking, which is a major obstacle for further improvements in diagnosis and therapy. The present study focuses on the effects of enzyme replacement therapy on a previously established podocyte cell culture model of Fabry disease. METHODS: We investigated the effect of in vitro application of α-Gal A on Fabry podocytes for 3 days, mimicking enzyme replacement therapy. We studied reduction of Gb3 levels and dysregulated molecular pathways such as autophagy, mTOR/AKT signaling and pro-fibrotic signaling by employing immunofluorescence, electron microscopy, tandem mass spectrometry and western blot. RESULTS: We detected complete resolution of Gb3 accumulation in Fabry podocytes upon α-Gal A treatment. Despite robust Gb3 clearance, dysregulation of the signaling pathways investigated was not reversed. CONCLUSION: This study presents first evidence for Gb3-independent effects regarding dysregulation of signal transduction mechanisms in FD not recovering upon α-Gal A treatment. We assume that intracellular alterations observed in FD may have a point of no return after which a reversal of dysregulated cellular signal transduction by α-Gal A treatment is not effective, despite Gb3 clearance. Our observations suggest further research on signal transduction mechanisms altered in Fabry podocytes and on determining the appropriate time for initiation of Fabry therapy.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry , Modelos Biológicos , Podocitos/metabolismo , Transducción de Señal/efectos de los fármacos , Trihexosilceramidas/metabolismo , alfa-Galactosidasa/uso terapéutico , Técnicas de Cultivo de Célula , Línea Celular Transformada , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/metabolismo , Enfermedad de Fabry/patología , Humanos , Podocitos/patología
12.
Mol Genet Metab ; 127(1): 86-94, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30987917

RESUMEN

BACKGROUND: Fabry disease is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose agalsidase beta regimens to lower skin, plasma, and urine globotriaosylceramide (GL-3) levels, and influence clinical manifestations in male pediatric Fabry patients. METHODS: In this multicenter, open-label, parallel-group, phase 3b study, male patients aged 5-18 years were randomized to receive agalsidase beta at 0.5 mg/kg 2-weekly (n = 16) or 1.0 mg/kg 4-weekly (n = 15) for 5 years. All had plasma/urine GL-3 accumulation but no clinically evident organ involvement. The primary outcome was GL-3 accumulation in superficial skin capillary endothelium (SSCE). RESULTS: The mean age was 11.6 (range: 5-18) years and all but one of the 31 patients had classic GLA mutations. In the overall cohort, shifts from non-0 to 0-scores for SSCE GL-3 were significant at years 1, 3, and 5, but results were variable. Plasma GL-3 normalized and urine GL-3 reduced substantially. Higher anti-agalsidase beta antibody titers were associated with less robust SSCE GL-3 clearance and higher urine GL-3 levels. Renal function remained stable and normal. Most Fabry signs and symptoms tended to stabilize; abdominal pain was significantly reduced (-26.3%; P = .0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (n = 7). Treatment effects on podocyte GL-3 content and foot process width were highly variable. Fabry arteriopathy overall increased in severity. Two patients withdrew and 2 had their agalsidase beta dose increased. CONCLUSIONS: Our findings increase the limited amount of available data on long-term effects of enzyme replacement therapy in pediatric, classic Fabry patients. The low-dose regimens studied here over a period of 5 years did not demonstrate a consistent benefit among the patients in terms of controlling symptomatology, urine GL-3 levels, and pathological histology. The current available evidence supports treatment of pediatric, classic male Fabry patients at the approved agalsidase beta dose of 1.0 mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with agalsidase beta.


Asunto(s)
Terapia de Reemplazo Enzimático/estadística & datos numéricos , Enfermedad de Fabry/tratamiento farmacológico , Isoenzimas/uso terapéutico , alfa-Galactosidasa/uso terapéutico , Adolescente , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Piel/química , Piel/patología , Resultado del Tratamiento , Trihexosilceramidas/análisis
14.
Mol Genet Metab ; 126(4): 448-459, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30803893

RESUMEN

Fabry disease is a rare X-linked inherited multisystem disorder resulting from deficiency of the lysosomal enzyme alpha-galactosidase A. Currently, specific therapies, including enzyme replacement therapies, are available for Fabry disease, but clinical trials provide limited information on long-term safety and effectiveness. Agalsidase alfa was approved in Japan in 2006. The post-marketing surveillance study of all patients receiving agalsidase alfa to evaluate its long-term safety and effectiveness as a mandatory condition for its approval had been conducted for 8 years (from February 2007 to March 2015). A total of 493 patients were included in this analysis of safety and effectiveness. The overall mean follow-up period was 3.5 years (range, 0.0-7.9 years). The percentage of patients with adverse drug reactions was 24.5% (121/493) and 12.6% had infusion-related reactions (62/493). In the 256 patients without prior enzyme replacement therapy whose IgG antibody data were available, 17 were IgG antibody positive (6.6%). However, the chronological correlation between seroconversion and the incidence of infusion-related reactions was not clear. The mean brief pain inventory score of the worst pain decreased in patients with moderate and severe pain at baseline. Plasma Gb3 and urine sediment Gb3 in males with classical Fabry disease without prior enzyme replacement therapy significantly decreased. The mean yearly changes in eGFR (mL/min/1.73 m2) ranged from -2.88 to +1.00 in males with classical Fabry disease, from -2.04 to -0.95 in males with non-typical variant and from -2.64 to -1.02 in females. The lower eGFR or the more proteinuria at baseline, the faster the decrease in eGFR of the patients was observed. There was no substantial difference in cardiac parameters (left ventricular mass index, E/A wave ratio, ejection fraction, and QRS duration). In conclusion, agalsidase alfa, 0.2 mg/kg every other week, was well tolerated and controlled the progression of symptoms (especially renal and cardiac) of Fabry disease in adults. Enzyme replacement therapy should be started in Japanese patients before cardiac and/or renal symptoms of Fabry disease develop.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Isoenzimas/uso terapéutico , Vigilancia de Productos Comercializados , Proteínas Recombinantes/uso terapéutico , alfa-Galactosidasa/uso terapéutico , Adolescente , Adulto , Anciano , Niño , Preescolar , Terapia de Reemplazo Enzimático/efectos adversos , Femenino , Corazón/efectos de los fármacos , Corazón/fisiopatología , Humanos , Inmunoglobulina G/sangre , Isoenzimas/efectos adversos , Japón , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Dolor , Proteínas Recombinantes/efectos adversos , Resultado del Tratamiento , Adulto Joven , alfa-Galactosidasa/efectos adversos
15.
Orphanet J Rare Dis ; 14(1): 4, 2019 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-30616652

RESUMEN

Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies with agalsidase alfa and beta have been available. In this letter we underline the different clinical and technical considerations the readers have to be aware of to interpret the results of studies dealing with Fabry disease and anti-agalsidase antibodies. We reaffirm that antibodies preferentially develop in the severe classic Fabry phenotype, which can mislead into interpreting that antibodies are associated with much severe clinical events.


Asunto(s)
Enfermedad de Fabry/enzimología , Enfermedad de Fabry/patología , Anticuerpos/uso terapéutico , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Femenino , Humanos , Masculino , alfa-Galactosidasa/antagonistas & inhibidores , alfa-Galactosidasa/metabolismo , alfa-Galactosidasa/uso terapéutico
16.
PLoS One ; 14(1): e0210617, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30633777

RESUMEN

The major cellular clearance pathway for organelle and unwanted proteins is the autophagy-lysosome pathway (ALP). Lysosomes not only house proteolytic enzymes, but also traffic organelles, sense nutrients, and repair mitochondria. Mitophagy is initiated by damaged mitochondria, which is ultimately degraded by the ALP to compensate for ATP loss. While both systems are dynamic and respond to continuous cellular stressors, most studies are derived from animal models or cell based systems, which do not provide complete real time data about cellular processes involved in the progression of lysosomal storage diseases in patients. Gaucher and Fabry diseases are rare sphingolipid disorders due to the deficiency of the lysosomal enzymes; glucocerebrosidase and α-galactosidase A with resultant lysosomal dysfunction. Little is known about ALP pathology and mitochondrial function in patients with Gaucher and Fabry diseases, and the effects of enzyme replacement therapy (ERT). Studying blood mononuclear cells (PBMCs) from patients, we provide in vivo evidence, that regulation of ALP is defective. In PBMCs derived from Gaucher patients, we report a decreased number of autophagic vacuoles with increased cytoplasmic localization of LC3A/B, accompanied by lysosome accumulation. For both Gaucher and Fabry diseases, the level of the autophagy marker, Beclin1, was elevated and ubiquitin binding protein, SQSTM1/p62, was decreased. mTOR inhibition did not activate autophagy and led to ATP inhibition in PBMCs. Lysosomal abnormalities, independent of the type of the accumulated substrate suppress not only autophagy, but also mitochondrial function and mTOR signaling pathways. ERT partially restored ALP function, LC3-II accumulation and decreased LC3-I/LC3-II ratios. Levels of lysosomal (LAMP1), autophagy (LC3), and mitochondrial markers, (Tfam), normalized after ERT infusion. In conclusion, there is mTOR pathway dysfunction in sphingolipidoses, as observed in both PBMCs derived from patients with Gaucher and Fabry diseases, which leads to impaired autophagy and mitochondrial stress. ERT partially improves ALP function.


Asunto(s)
Autofagia/fisiología , Terapia de Reemplazo Enzimático/métodos , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/uso terapéutico , Mitofagia/fisiología , alfa-Galactosidasa/uso terapéutico , Adolescente , Adulto , Anciano , Animales , Niño , Enfermedad de Fabry/enzimología , Enfermedad de Fabry/fisiopatología , Femenino , Enfermedad de Gaucher/enzimología , Enfermedad de Gaucher/fisiopatología , Humanos , Leucocitos Mononucleares/metabolismo , Lisosomas/metabolismo , Masculino , Persona de Mediana Edad , Transducción de Señal , Adulto Joven
17.
Mol Genet Metab ; 126(2): 162-168, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30473480

RESUMEN

BACKGROUND: Treatment of Fabry disease (FD) with recombinant alpha-galactosidase A (r-αGAL A) is complicated by the formation of anti-drug antibodies in the majority of male patients with the classical disease phenotype. Detailed information regarding antibody subtypes, onset and persistence of antibody development and their effect on treatment efficacy is sparse. METHODS: A retrospective study was carried out in 39 male patients with classical FD, treated with either agalsidase-alfa or agalsidase-beta (mean follow up of 10 years). With six to twelve months intervals plasma-induced in vitro inhibition of enzyme activity, lysoglobotriaosylsphingosine (lysoGb3) levels and renal function were assessed. In a subset of 12 patients, additionally anti- r-αGAL A IgM, IgA and IgG1, 2, 3 and 4 levels were analyzed. RESULTS: In 23 out of 39 patients, plasma-induced in vitro inhibition of r-αGAL A activity was observed (inhibition-positive). The inhibition titer was strongly negatively correlated to the decrease in lysoGb3: agalsidase-alfa (FElog10(inhibition) = -10.3, P ≤.001), agalsidase-beta (FElog10(inhibition) = -4.7, P ≤.001). Inhibition-positive patients had an accelerated decline in renal function (FE = 1.21, p = .042). During treatment IgG1 anti-r-αGAL A levels increased only in inhibition-positive patients (p = .0045). IgG4 anti-r-αGAL A antibodies developed in 7 out of 9 inhibition-positive patients. Other antibody subclasses were either not present or too low to quantify. CONCLUSION: Development of inhibiting antibodies against r-αGAL A negatively affects the biochemical response to ERT and resulted in an accelerated decline in renal function. The presence of IgG1 and IgG4 anti-r-αGAL A antibodies is associated with in vitro αGAL A activity inhibition.


Asunto(s)
Anticuerpos/clasificación , Enfermedad de Fabry/tratamiento farmacológico , Isoenzimas/inmunología , Proteínas Recombinantes/inmunología , alfa-Galactosidasa/inmunología , Adolescente , Adulto , Anticuerpos/inmunología , Estudios de Seguimiento , Humanos , Inmunoglobulina G/inmunología , Isoenzimas/uso terapéutico , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven , alfa-Galactosidasa/uso terapéutico
18.
Int Heart J ; 60(1): 208-214, 2019 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-30464119

RESUMEN

Anderson-Fabry disease is a rare X-linked lysosomal storage disease caused by α-galactosidase A (α-GalA) gene variants and characterized by a large genotypic and phenotypic spectrum. Enzyme replacement therapy (ERT) using recombinant α-GalA has been approved for > 10 years as a specific therapy for the disease. However, the long-term clinical efficacy for cardiac manifestations has been equivocal because it depends on several factors such as genotype, sex, age, and disease severity at the initiation of ERT. We report the differences in the clinical effects of ERT continued for > 10 years in three patients with the same genotype. Left ventricular hypertrophy and myocardial dysfunction progressed in the heterozygote proband even under ERT, although disease progression was prevented in two sons of Case 1.


Asunto(s)
Terapia de Reemplazo Enzimático/métodos , Enfermedad de Fabry/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/etiología , Adulto , Fibrilación Atrial/complicaciones , Progresión de la Enfermedad , Ecocardiografía , Electrocardiografía , Enfermedad de Fabry/enzimología , Enfermedad de Fabry/genética , Femenino , Insuficiencia Cardíaca/complicaciones , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/fisiopatología , Isoenzimas/administración & dosificación , Isoenzimas/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Resultado del Tratamiento , alfa-Galactosidasa/administración & dosificación , alfa-Galactosidasa/genética , alfa-Galactosidasa/uso terapéutico
19.
Mol Genet Metab ; 126(3): 224-235, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30413388

RESUMEN

BACKGROUND: Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients. METHODS: A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type. RESULTS: Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease. CONCLUSIONS: This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry/terapia , Ensayos Clínicos como Asunto , Femenino , Tracto Gastrointestinal , Humanos , Isoenzimas/uso terapéutico , Sistema Nervioso , Estudios Observacionales como Asunto , Dolor , Calidad de Vida , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , Trihexosilceramidas/sangre , Trihexosilceramidas/orina , alfa-Galactosidasa/uso terapéutico
20.
Mol Genet Metab ; 126(3): 212-223, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-29785937

RESUMEN

BACKGROUND: Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease. METHODS: A comprehensive systematic review of published literature on ERT in Fabry disease was conducted in January 2017. The literature analysis included all original articles reporting outcomes of ERT in paediatric patients. RESULTS: Treatment-related outcomes in the paediatric population were reported in six publications derived from open-label clinical trials and in 10 publications derived from observational or registry-based studies. ERT was shown to significantly reduce plasma and urine GL-3 levels in paediatric patients with Fabry disease. The effect of ERT on GL-3 clearance from renal podocytes appeared to be agalsidase dose-dependent. ERT relieved pain and improved gastrointestinal symptoms and quality of life. CONCLUSIONS: Based on the published literature, the use of ERT in paediatric patients can significantly clear GL-3 accumulation, ameliorate the early symptoms of Fabry disease, and improve quality of life. Treatment with ERT in paediatric patients with Fabry disease may be important to prevent further disease progression and overt organ damage.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry/terapia , Niño , Europa (Continente) , Femenino , Humanos , Isoenzimas/uso terapéutico , Masculino , Estudios Observacionales como Asunto , Dolor/tratamiento farmacológico , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , Trihexosilceramidas/metabolismo , alfa-Galactosidasa/uso terapéutico
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