Diet and Physical Activity in Fabry Disease: A Narrative Review.

Fabry disease (FD) is caused by mutations in the galactosidase alpha (GLA) gene which lead to the accumulation of globotriaosylceramide (Gb-3). Enzyme replacement therapy (ERT) and oral chaperone therapy are the current pharmacological treatments for this condition. However, in the literature, there is a growing emphasis on exploring non-pharmacological therapeutic strategies to improve the quality of life of patients with FD. In particular, the nutritional approach to FD has been marginally addressed in the scientific literature, although specific dietary interventions may be useful for the management of nephropathy and gastrointestinal complications, which are often present in patients with FD. Especially in cases of confirmed diagnosis of irritable bowel syndrome (IBS), a low-FODMAP diet can represent an effective approach to improving intestinal manifestations. Furthermore, it is known that some food components, such as polyphenols, may be able to modulate some pathogenetic mechanisms underlying the disease, such as inflammation and oxidative stress. Therefore, the use of healthy dietary patterns should be encouraged in this patient group. Sports practice can be useful for patients with multi-organ involvement, particularly in cardiovascular, renal, and neurological aspects. Therefore, the aim of this review is to summarize current knowledge on the role of nutrition and physical activity in FD patients.

Therapeutic Strategy for Fabry Disease by Intravenous Administration of Adeno-Associated Virus 9 in a Symptomatic Mouse Model.

Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α-galactosidase A (α-Gal A), an enzyme that hydrolyzes glycosphingolipids in lysosome. Accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in tissues, induces cellular dysfunction leading to multi-organ disorder. Gene therapy is a promising strategy that can overcome these problems, and virus vectors such as adeno-associated virus (AAV) have been used for study on gene therapy. We used human Gb3 synthetase-transgenic (TgG3S)/α-Gal A knockout (GLAko) mice. TgG3S/GLAko mice have elevated Gb3 accumulation in the major organs compared with GLAko mice, which have been widely used as a model for FD. At the age of 6 weeks, male TgG3S/GLAko were injected with 2 × 1012 vector genome AAV9 vectors containing human α-Gal A cDNA. Eight weeks after intravenous injection of AAV, α-Gal A enzymatic activity was elevated in the plasma, heart, and liver of TgG3S/GLAko mice to levels corresponding to 224%, 293%, and 105% of wild-type, respectively. Gb3 amount 8 weeks after AAV injection in the heart and liver of this group was successfully reduced to levels corresponding to 16% and 3% of untreated TgG3S/GLAko mice. Although the brain and kidney of AAV9-treated TgG3S/GLAko mice showed no significant increases in α-Gal A activity, Gb3 amount was smaller than untreated littermates (48% and 44%, respectively). In this study, systemic AAV administration did not show significant extension of the lifespan of TgG3S/GLAko mice compared with the untreated littermates. The timing of AAV injection, capsid choice, administration route, and injection volume may be important to achieve sufficient expression of α-Gal A in the whole body for the amelioration of lifespan.

Fabry Disease: Cardiac Implications and Molecular Mechanisms.

PURPOSE OF REVIEW: This review explores the interplay among metabolic dysfunction, oxidative stress, inflammation, and fibrosis in Fabry disease, focusing on their potential implications for cardiac involvement. We aim to discuss the biochemical processes that operate in parallel to sphingolipid accumulation and contribute to disease pathogenesis, emphasizing the importance of a comprehensive understanding of these processes. RECENT FINDINGS: Beyond sphingolipid accumulation, emerging studies have revealed that mitochondrial dysfunction, oxidative stress, and chronic inflammation could be significant contributors to Fabry disease and cardiac involvement. These factors promote cardiac remodeling and fibrosis and may predispose Fabry patients to conduction disturbances, ventricular arrhythmias, and heart failure. While current treatments, such as enzyme replacement therapy and pharmacological chaperones, address disease progression and symptoms, their effectiveness is limited. Our review uncovers the potential relationships among metabolic disturbances, oxidative stress, inflammation, and fibrosis in Fabry disease-related cardiac complications. Current findings suggest that beyond sphingolipid accumulation, other mechanisms may significantly contribute to disease pathogenesis. This prompts the exploration of innovative therapeutic strategies and underscores the importance of a holistic approach to understanding and managing Fabry disease.

Hypertrophic Cardiomyopathy versus Storage Diseases with Myocardial Involvement.

One of the main causes of heart failure is cardiomyopathies. Among them, the most common is hypertrophic cardiomyopathy (HCM), characterized by thickening of the left ventricular muscle. This article focuses on HCM and other cardiomyopathies with myocardial hypertrophy, including Fabry disease, Pompe disease, and Danon disease. The genetics and pathogenesis of these diseases are described, as well as current and experimental treatment options, such as pharmacological intervention and the potential of gene therapies. Although genetic approaches are promising and have the potential to become the best treatments for these diseases, further research is needed to evaluate their efficacy and safety. This article describes current knowledge and advances in the treatment of the aforementioned cardiomyopathies.

GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals.

Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the galactosidase alpha (GLA), which codes for α-Galactosidase A (α-GAL) enzyme, in a human cardiac model generated from induced pluripotent stem cells (iPSCs) derived from two individuals with Fabry disease. Consistent with the clinical phenotype, cardiomyocytes from iPSCs derived from Fabry-affected individuals showed accumulation of the glycosphingolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate. Furthermore, the Fabry cardiomyocytes displayed significant upregulation of lysosomal-associated proteins. Upon GLA modRNA treatment, a subset of lysosomal proteins were partially restored to wild-type levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA-treated cardiomyocytes, demonstrating that α-GAL enzymatic activity was restored. Together, our results validate the utility of iPSC-derived cardiomyocytes from affected individuals as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart.

Therapeutic strategy for Fabry disease by intravenous administration of adeno-associated virus 2 or 9 in α-galactosidase A-deficient mice.

BACKGROUND: Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α-galactosidase A (α-Gal A) encoded by the GLA gene. The symptoms of FD occur as a result of the accumulation of globotriaosylceramide (Gb3), comprising a substrate of α-Gal A, in the organs. Adeno-associated virus (AAV)-mediated gene therapy is a promising treatment for FD. METHODS: α-Gal A knockout (GLAko) mice were injected intravenously with AAV2 (1 × 1011 viral genomes [vg]) or AAV9 (1 × 1011 or 2 × 1012 vg) vectors carrying human GLA (AAV-hGLA), and plasma, brain, heart, liver and kidney were tested for α-Gal A activity. The vector genome copy numbers (VGCNs) and Gb3 content in each organ were also examined. RESULTS: The plasma α-Gal A enzymatic activity was three-fold higher in the AAV9 2 × 1012 vg group than wild-type (WT) controls, which was maintained for up to 8 weeks after injection. In the AAV9 2 × 1012 vg group, the level of α-Gal A expression was high in the heart and liver, intermediate in the kidney, and low in the brain. VGCNs in the all organs of the AAV9 2 × 1012 vg group significantly increased compared to the phosphate-buffered-saline (PBS) group. Although Gb3 in the heart, liver and kidney of the AAV9 2 × 1012 vg was reduced compared to PBS group and AAV2 group, and the amount of Gb3 in the brain was not reduced. CONCLUSIONS: Systemic injection of AAV9-hGLA resulted in α-Gal A expression and Gb3 reduction in the organs of GLAko mice. To expect a higher expression of α-Gal A in the brain, the injection dosage, administration route and the timing of injection should be reconsidered.

Investigation of bone mineral density and the changes by enzyme replacement therapy in patients with Fabry disease.

BACKGROUND: Fabry disease (FD) is an inherited disorder that causes organ dysfunction. However, only a few studies have reported on bone mineral density (BMD) in FD patients, and the relationship between BMD and clinical factors such as globotriaosylsphingosine (lyso-Gb3) remains unclear. Therefore, the current study sought to investigate BMD in FD patients, the relationship between BMD and lyso-Gb3, and the effects of enzyme replacement therapy (ERT) on changes in BMD and lyso-Gb3. METHODS: This single-center, observational study included 15 patients who visited our facility for FD between January 2008 and June 2021. We assessed BMD and clinical characteristics in study patients, including plasma lyso-Gb3 levels, and examined the relationship between BMD and plasma lyso-Gb3 levels, and changes in BMD after starting ERT. RESULTS: Male patients' BMD had reduced, whereas female patients' BMD was preserved. Male patients had significantly higher plasma lyso-Gb3 levels than female patients. Moreover, plasma lyso-Gb3 levels were found to be significantly related to the lumbar spine and femoral BMD. These were strongly linked with plasma lyso-Gb3 levels in male patients, whereas no strong link was observed in female patients. Furthermore, BMD significantly increased only in male patients although plasma lyso-Gb3 levels significantly decreased by ERT in all patients. CONCLUSION: BMD decreased possibly due to Gb3 accumulation, and ERT could increase BMD in male FD patients.

In Vivo Delivery of Therapeutic Molecules by Transplantation of Genome-Edited Induced Pluripotent Stem Cells.

Human induced pluripotent stem cells (iPSCs) have already been used in transplantation therapies. Currently, cells from healthy people are transplanted into patients with diseases. With the rapid evolution of genome editing technology, genetic modification could be applied to enhance the therapeutic effects of iPSCs, such as the introduction of secreted molecules to make the cells a drug delivery system. Here, we addressed this possibility by utilizing a Fabry disease mouse model, as a proof of concept. Fabry disease is caused by the lack of α-galactosidase A (GLA). We previously developed an immunotolerant therapeutic molecule, modified α-N-acetylgalactosaminidase (mNAGA). We confirmed that secreted mNAGA from genome-edited iPSCs compensated for the GLA activity in GLA-deficient cells using an in vitro co-culture system. Moreover, iPSCs transplanted into Fabry model mice secreted mNAGA and supplied GLA activity to the liver. This study demonstrates the great potential of genome-edited iPSCs secreting therapeutic molecules.

Diagnosis and Management of Fabry Disease in High-Risk Renal Disease Patients in Taiwan: A Single Center Study.

BACKGROUND: Fabry disease (FD) is an X-linked inborn error of lysosomal storage disorder, a deficiency in lysosomal hydrolase α-galactosidase A activity due to pathogenic variants in the GLA gene. Accumulation of globotriaosylceramide in multiple organs contributes to end-stage kidney disease, heart failure, and cerebrovascular accidents. METHODS: We began the FD screening program by involving male patients older than 20 years of age who were on chronic dialysis, had a post-kidney transplantation, and were part of the Pre-End Stage Renal Disease Program in our hospital. α-galactosidase A activity was detected through an initial dried blood spots screen assay, followed by levels of lyso-globotriaosylceramide and sequencing of the GLA gene when screening patients with suspected FD to confirm their diagnosis. RESULTS: A total of 1812 patients had been FD screened, with the prevalence of FD being approximately 0.16 % (3/1812) up until June 2022. Interestingly, we confirmed a family cluster (2 sons and their mother) of having the c.936+919G>A mutation (designated GLA IVS4) with hypertrophic cardiomyopathy in Taiwan and another with the mutation c.644A>G (p.Asn215Ser), a more common later-onset variant reported in people of European or North American descent. Two patients were confirmed with cardiomyopathy through a cardiac biopsy, with their cardiac function later reversed after enzyme replacement therapy. CONCLUSIONS: The FD screening test detects chronic kidney disease due to an unknown etiology and prevents other organ complications. Early detection of FD is crucial for reversing target organ damage with enzyme replacement therapy.

Preclinical evaluation of FLT190, a liver-directed AAV gene therapy for Fabry disease.

Fabry disease is an X-linked lysosomal storage disorder caused by loss of alpha-galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of glycosphingolipids in multiple cells and tissues. FLT190, an investigational gene therapy, is currently being evaluated in a Phase 1/2 clinical trial in patients with Fabry disease (NCT04040049). FLT190 consists of a potent, synthetic capsid (AAVS3) containing an expression cassette with a codon-optimized human GLA cDNA under the control of a liver-specific promoter FRE1 (AAV2/S3-FRE1-GLAco). For mouse studies FLT190 genome was pseudotyped with AAV8 for efficient transduction. Preclinical studies in a murine model of Fabry disease (Gla-deficient mice), and non-human primates (NHPs) showed dose-dependent increases in plasma α-Gal A with steady-state observed 2 weeks following a single intravenous dose. In Fabry mice, AAV8-FLT190 treatment resulted in clearance of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in plasma, urine, kidney, and heart; electron microscopy analyses confirmed reductions in storage inclusion bodies in kidney and heart. In NHPs, α-Gal A expression was consistent with the levels of hGLA mRNA in liver, and no FLT190-related toxicities or adverse events were observed. Taken together, these studies demonstrate preclinical proof-of-concept of liver-directed gene therapy with FLT190 for the treatment of Fabry disease.

Integrating Cardiac MRI Imaging and Multidisciplinary Clinical Care is Associated With Improved Outcomes in Patients With Fabry Disease.

Given the inherent complexities of Fabry disease (FD) and evolving landscape of cardiovascular clinical management, there is no established ideal clinical care model for these patients. We identified clinical factors predictive of increased risk of major adverse cardiac events (MACE) in patients with FD targeted to improve clinical outcomes. Ninety-five patients studied over a median follow-up time of 6.3 years, and 26 patients reached the composite endpoint with a high prevalence of heart failure and cerebrovascular events and no cardiac-related mortality. Patients with MACE had worse health-related quality of life scores. Hypertrophy and presence of myocardial fibrosis increase risk of MACE by 4-5 times, and dyslipidemia increases risk of MACE by 3 times. Early Fabry-specific treatment and close monitoring of comorbidities reduce cardiac complications and mortality. These findings highlight the importance of comprehensive multidisciplinary management to help improve outcomes in FD patients.

An Overview of Molecular Mechanisms in Fabry Disease.

Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is α-galactosidase A (α-Gal A), which is due to a mutation in the GLA gene on the X chromosome. The enzyme deficiency leads to a continuous deposition of neutral glycosphingolipids (globotriaosylceramide) in the lysosomes of numerous tissues and organs, including endothelial cells, smooth muscle cells, corneal epithelial cells, renal glomeruli and tubules, cardiac muscle and ganglion cells of the nervous system. This condition leads to progressive organ failure and premature death. The increasing understanding of FD, and LSD in general, has led in recent years to the introduction of enzyme replacement therapy (ERT), which aims to slow, if not halt, the progression of the metabolic disorder. In this review, we provide an overview of the main features of FD, focusing on its molecular mechanism and the role of biomarkers.

Patients' view on gene therapy development for lysosomal storage disorders: a qualitative study.

INTRODUCTION: Several new treatment modalities are being developed for lysosomal storage disorders (LSDs), including gene therapy. As the currently available treatment options and their influence on disease progression differ greatly within the spectrum of LSDs, willingness to undergo gene therapy might vary among patients with LSDs and/or their representatives. The width of the LSD spectrum is illustrated by the differences between type 1 Gaucher disease, Fabry disease and Mucopolysaccharidosis type III (MPS III). For type 1 Gaucher and Fabry disease several therapies are available, resulting in a near normal or improved, but individually varying, prognosis. No treatment options are available for MPS III. AIM: To identify factors influencing patients' and/or their representatives' decisions regarding undergoing gene therapy. METHODS: Focus group discussions and semi-structured interviews were conducted with patients with type 1 Gaucher disease, Fabry disease and MPS III. Parents of MPS III patients were included as patients' representatives. RESULTS: Nine Gaucher patients, 23 Fabry patients, two adult MPS III patients and five parents of MPS III patients participated in the study. The five main themes that arose were: outcome of gene therapy, risks and side effects, burden of gene therapy treatment, current situation and ethical aspects. Participants' views ranged from hesitance to eagerness to undergo gene therapy, which seemed to be mostly related to disease severity and currently available treatment options. Severe disease, limited treatment options and limited effectiveness of current treatment augmented the willingness to choose gene therapy. Gaucher and Fabry patients deemed the burden of treatment important. Fabry and MPS III patients and parents considered outcome important, suggesting hope for improvement. When asked to rank the factors discussed in the focus group discussions, Gaucher patients ranked outcome low, which could indicate a more cautious attitude towards gene therapy. CONCLUSION: This study underlines the importance of exploring patients' needs and expectations before using limited resources in the development of therapies for patient groups of which a significant subset may not be willing to undergo that specific therapy.

An expert consensus on practical clinical recommendations and guidance for patients with classic Fabry disease.

Fabry disease is an X-linked inherited lysosomal disorder that causes accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and reduced life expectancy. It can affect both males and females and can be classified into classic or later-onset phenotypes. In classic Fabry disease, α-galactosidase A (α-Gal A) activity is absent or severely reduced and disease manifestations have an early onset that can affect multiple organs. In contrast, in later-onset Fabry disease, patients have residual α-Gal A activity and clinical features are primarily confined to the heart. Individualized therapeutic goals in Fabry disease are required due to varying phenotypes and patient characteristics, and the wide spectrum of disease severity. An international group of expert physicians convened to discuss and develop practical clinical recommendations for disease- and organ-specific therapeutic goals in Fabry disease, based on expert consensus and evidence identified through a structured literature review. Biomarkers reflecting involvement of various organs in adult patients with classic Fabry disease are discussed and consensus recommendations for disease- and organ-specific therapeutic goals are provided. These consensus recommendations should support the establishment of individualized approaches to the management of patients with classic Fabry disease by considering identification, diagnosis, and initiation of disease-specific therapies before significant organ involvement, as well as routine monitoring, to reduce morbidity, optimize patient care, and improve patient health-related quality of life.

7th Update on Fabry Disease: Biomarkers, Progression and Treatment Opportunities in 2022.

no abstract.