Pegunigalsidase alfa: a novel, pegylated recombinant alpha-galactosidase enzyme for the treatment of Fabry disease

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 15

Published: April 12, 2024

Fabry disease, a rare X-linked genetic disorder, results from pathogenic variants in GLA , leading to deficient lysosomal α-galactosidase A enzyme activity and multi-organ manifestations. Since 2001, replacement therapy (ERT), using agalsidase alfa or beta, has been the mainstay treatment, albeit with limitations such as rapid clearance immunogenicity. Pegunigalsidase alfa, novel PEGylated recombinant alpha-galactosidase, offers promise an alternative. Produced plant cells, pegunigalsidase exhibits enhanced stability, prolonged half-life, reduced immunogenicity due pegylation. phase 1/2 clinical trial demonstrated Gb3 renal capillary endothelial cells its 48-month extension study revealed notable outcomes function preservation. Three 3 trials (BRIDGE, BRIGHT, BALANCE) have shown favorable efficacy safety profile, although caution is warranted interpreting of BRIDGE BRIGHT which lacked control groups. In BALANCE, pivotal comparing intention-to-treat analysis eGFR decline over 2 years showed that intergroup difference [95%confidence interval] median slope was −0.36 mL/min/1.73 m /year [−2.44; 1.73]. The confidence interval had lower limit above prespecified value −3 included zero. Despite challenges occasional hypersensitivity reactions immune-complex-mediated glomerulonephritis, approval by European Medicines Agency Food Drug Administration represents significant addition disease therapeutic landscape providing option for patients whom current formulations poorly tolerated effective.

Language: Английский

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The importance of a multidisciplinary approach in two tricky cases: the perfect match for Fabry disease

BMC Nephrology, Journal Year: 2025, Volume and Issue: 26(1)

Published: Feb. 13, 2025

Language: Английский

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Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association

Stroke, Journal Year: 2023, Volume and Issue: 54(10)

Published: Aug. 21, 2023

Lacunar infarcts and vascular dementia are important phenotypic characteristics of cerebral autosomal dominant arteriopathy with subcortical leukoencephalopathy, the most common inherited small vessel disease. Individuals disease show variability in nature onset symptoms rates progression, which only partially explained by differences pathogenic mutations NOTCH3 gene. Recognizing early its course securing a molecular diagnosis clinical goals, despite lack proven disease-modifying treatments. The purposes this scientific statement to review clinical, genetic, imaging aspects contrasting it other diseases, provide key prevention, management, therapeutic considerations intent reducing practice encouraging production high-quality evidence support future treatment recommendations.

Language: Английский

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EMQN: Recommendations for genetic testing in inherited cardiomyopathies and arrhythmias

European Journal of Human Genetics, Journal Year: 2023, Volume and Issue: 31(9), P. 1003 - 1009

Published: July 13, 2023

Abstract Inherited cardiomyopathies and arrhythmias (ICAs) are a prevalent clinically heterogeneous group of genetic disorders that associated with increased risk sudden cardiac death heart failure. Making diagnosis can inform the management patients their at-risk relatives and, as such, molecular testing is now considered an integral component clinical care pathway. However, ICAs characterised by high allelic heterogeneity, incomplete / age-related penetrance, variable expressivity. Therefore, despite our improved understanding basis these conditions, significant technological advances over past two decades, identifying recognising causative genotype remains challenging. As for becomes more widely available, it increasingly important laboratories to consolidate existing knowledge experience improve future practice. These recommendations have been compiled help navigate challenges thereby facilitate best practice consistency in test provision this disorders. General on internal external quality control, referral, analysis, result interpretation, reporting described. Also included appendices provide specific information pertinent hypertrophic, dilated, arrhythmogenic right ventricular cardiomyopathies, long QT syndrome, Brugada catecholaminergic polymorphic tachycardia.

Language: Английский

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Anderson-Fabry disease cardiomyopathy: an update on epidemiology, diagnostic approach, management and monitoring strategies

Frontiers in Cardiovascular Medicine, Journal Year: 2023, Volume and Issue: 10

Published: June 2, 2023

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by deficient activity of the enzyme alpha-galactosidase. While AFD recognized as a progressive multi-system disorder, infiltrative cardiomyopathy causing number cardiovascular manifestations important complication this disease. affects both men and women, although clinical presentation typically varies sex, with presenting at younger age more neurologic renal phenotype women developing later onset variant manifestations. cause increased myocardial wall thickness, advances in imaging, particular cardiac magnetic resonance imaging T1 mapping techniques, have improved ability to identify non-invasively. Diagnosis confirmed presence low alpha-galactosidase identification mutation GLA gene. Enzyme replacement therapy remains mainstay modifying therapy, two formulations currently approved. In addition, newer treatments such oral chaperone are now available for select patients, other investigational therapies development. The availability these has significantly outcomes patients. Improved survival multiple agents presented new dilemmas regarding monitoring surveillance using clinical, laboratory biomarkers, addition approaches managing risk factors complications. This review will provide update on recognition diagnostic including differentiation from causes ventricular modern strategies management follow-up.

Language: Английский

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Newborn Screening for Fabry Disease: Current Status of Knowledge

International Journal of Neonatal Screening, Journal Year: 2023, Volume and Issue: 9(2), P. 31 - 31

Published: June 5, 2023

Fabry disease is an X-linked progressive lysosomal disorder, due to α-galactosidase A deficiency. Patients with a classic phenotype usually present in childhood as multisystemic disease. presenting the later onset subtypes have cardiac, renal and neurological involvements adulthood. Unfortunately, diagnosis often delayed until organ damage already irreversibly severe, making specific treatments less efficacious. For this reason, last two decades, newborn screening has been implemented allow early treatment. This became possible application of standard enzymology fluorometric method dried blood spots. Then, high-throughput multiplexable assays, such digital microfluidics tandem mass spectrometry, were developed. Recently DNA-based methods applied some countries. Using these methods, several pilot studies programs worldwide. However, concerns persist, for still not universally accepted. In particular, enzyme-based miss relevant number affected females. Moreover, ethical issues are large infants forms or variants uncertain significance. Long term follow-up individuals detected by will improve our knowledge about natural history disease, prediction patients’ management, allowing better evaluation risks benefits

Language: Английский

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Assessing brain involvement in Fabry disease with deep learning and the brain‐age paradigm

Human Brain Mapping, Journal Year: 2024, Volume and Issue: 45(5)

Published: March 23, 2024

Abstract While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement lacking. We used deep learning and the brain‐age paradigm assess whether FD patients' brains appear older than normal validate brain‐predicted age difference (brain‐PAD) as a possible severity biomarker. MRI scans patients healthy controls (HCs) from single Institution were, retrospectively, studied. The stabilization index (FASTEX) was recorded severity. Using minimally preprocessed 3D T1‐weighted subjects eight publicly available sources ( N = 2160; mean 33 years [range 4–86]), we trained model predicting chronological based on DenseNet architecture it generate predictions in internal cohort. Within linear modeling framework, brain‐PAD tested for age/sex‐adjusted associations with diagnostic group (FD vs. HC), FASTEX score, both global voxel‐level measures. studied 52 (40.6 ± 12.6 years; 28F) 58 HC (38.4 13.4 28F). achieved accurate out‐of‐sample performance (mean absolute error 4.01 years, R 2 .90). had significantly higher (estimated marginal means: 3.1 −0.1, p .01). Brain‐PAD associated score B 0.10, .02), parenchymal fraction −153.50, .001), white matter hyperintensities load 0.85, .01), tissue volume reduction throughout brain. demonstrated that normal. correlates FD‐related multi‐organ damage is influenced by hyperintensities, offering comprehensive biomarker (neurological)

Language: Английский

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Italian Association of Hospital Cardiologists Position Paper ‘Gender discrepancy: time to implement gender-based clinical management’

European Heart Journal Supplements, Journal Year: 2024, Volume and Issue: 26(Supplement_2), P. ii264 - ii293

Published: April 1, 2024

It has been well assessed that women have widely under-represented in cardiovascular clinical trials. Moreover, a significant discrepancy pharmacological and interventional strategies reported. Therefore, poor outcomes more mortality shown many diseases. Pharmacokinetic pharmacodynamic differences drug metabolism also described so effectiveness could be different according to sex. However, awareness about the gender gap remains too scarce. Consequently, gender-specific guidelines are lacking, need for sex-specific approach become evident last few years. This paper aims evaluate therapeutic approaches managing most common women's

Language: Английский

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A systematic literature review on the health-related quality of life and economic burden of Fabry disease

Orphanet Journal of Rare Diseases, Journal Year: 2024, Volume and Issue: 19(1)

Published: April 30, 2024

Abstract Background Fabry disease (FD) is a rare lysosomal storage associated with glycolipid accumulation that impacts multiple physiological systems. We conducted systematic literature review (SLR) to characterize the humanistic (quality of life [QoL]) and economic burden FD. Methods Searches were in Embase, MEDLINE ® , In-Process databases from inception January 19, 2022. Conference abstracts specified congresses manually searched. Additional searches performed Cochrane ProQuest for SLR National Health Service Economic Evaluations Database SLR. Studies patients FD any sex, race, age, published English language included. There was no restriction on intervention or comparator. For SLR, studies reported utility data, database/registry-based studies, questionnaires/surveys, cohort reporting evaluations assessing cost illness resource use Results Of 1363 records identified search, 36 The most commonly used QoL assessments 36-item Short-Form Survey (n = 16), EQ-5D questionnaire descriptive system visual analog scale 9), Brief Pain Inventory 8). Reduced compared healthy populations across domains, including pain, physical functioning, depressive symptoms. Multiple variables—including severity, treatment status—impacted QoL. 711 18 high healthcare use. Contributors included enzyme replacement therapy, healthcare, social care. In seven health values, lower scores generally more complications (including cardiac, renal, cerebrovascular morbidities) classical males. Conclusion remains burden, reduced populations. Integrating information may help identify interventions are likely be value

Language: Английский

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Plasma and platelet lipidome changes in Fabry disease

Clinica Chimica Acta, Journal Year: 2024, Volume and Issue: 562, P. 119833 - 119833

Published: June 30, 2024

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by the progressive accumulation of globotriaosylceramide (Gb3) leading to systemic manifestations such as chronic kidney disease, cardiomyopathy, and stroke. There still a need for novel markers improved FD screening prognosis. Moreover, pathological mechanisms in FD, which also include inflammation fibrosis, are not yet fully understood.

Language: Английский

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