Fabry disease: Mechanism and therapeutics strategies

Li, Xi; Ren, Xiangyi; Zhang, Yabing; Ding, Lin; Huo, Minfeng; Li, Qian

doi:10.3389/fphar.2022.1025740

Cited by 22 publications

(26 citation statements)

References 123 publications

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“…The central role of dysregulated autophagy in LSDs was proposed many years ago [ 73 ], and its predominance in FD was recently highlighted. In fact, autophagy is among the mechanisms that underlie the FD phenotype together with overall lysosomal dysfunction, lipid dysmetabolism, and inflammation [ 74 ]. Tens of different biological effects of curcumin have been described over the years, and more applications are still being recorded yearly [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

Curcumin Has Beneficial Effects on Lysosomal Alpha-Galactosidase: Potential Implications for the Cure of Fabry Disease

Monticelli

Mele

Allocca

et al. 2023

IJMS

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Fabry disease is a lysosomal storage disease caused by mutations in the GLA gene that encodes alpha-galactosidase (AGAL). The disease causes abnormal globotriaosylceramide (Gb3) storage in the lysosomes. Variants responsible for the genotypic spectrum of Fabry disease include mutations that abolish enzymatic activity and those that cause protein instability. The latter can be successfully treated with small molecules that either bind and stabilize AGAL or indirectly improve its cellular activity. This paper describes the first attempt to reposition curcumin, a nutraceutical, to treat Fabry disease. We tested the efficacy of curcumin in a cell model and found an improvement in AGAL activity for 80% of the tested mutant genotypes (four out of five tested). The fold-increase was dependent on the mutant and ranged from 1.4 to 2.2. We produced evidence that supports a co-chaperone role for curcumin when administered with AGAL pharmacological chaperones (1-deoxygalactonojirimycin and galactose). The combined treatment with curcumin and either pharmacological chaperone was beneficial for four out of five tested mutants and showed fold-increases ranging from 1.1 to 2.3 for DGJ and from 1.1 to 2.8 for galactose. Finally, we tested a long-term treatment on one mutant (L300F) and detected an improvement in Gb3 clearance and lysosomal markers (LAMP-1 and GAA). Altogether, our findings confirmed the necessity of personalized therapies for Fabry patients and paved the way to further studies and trials of treatments for Fabry disease.

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Section: Resultsmentioning

confidence: 99%

Curcumin Has Beneficial Effects on Lysosomal Alpha-Galactosidase: Potential Implications for the Cure of Fabry Disease

Monticelli

Mele

Allocca

et al. 2023

IJMS

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“…Abnormal GL-3 and lyso-GL-3 leaded to multi-system damage. [4] FD exhibits many phenotypes, ranging from severe early onset to mild or atypical late onset, and is associated with over 1000 genotypes. [5] Patients often have a variety of clinical signs and symptoms, mostly chronic or intermittent burning pain and sensory abnormalities in the extremities, impaired sweating (mostly manifesting as little or no sweating); cutaneous angiokeratomas in the lumbar region; radiolucent deposits visible under the corneal slit lamp, hearing loss and vestibular dysfunction; cardiac hypertrophy, cardiac conduction abnormalities, cardiac valve disease and heart failure; cerebrovascular and other organ involvement.…”

Section: Discussionmentioning

confidence: 99%

Case report and literature review: Fabry disease misdiagnosing as polymyalgia rheumatica

Yanfang,

Juanjuan,

Shengli

et al. 2023

Medicine

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Rationale: The clinical manifestations of Fabry disease affect the nerves, kidneys, heart, skin, gastrointestinal tract and eyes. Our aim is to familiarize people with the FD diagnostic process by reporting this case. Patient concerns: A 79-year-old-male patient presented with muscle pain and weakness in the extremities, also with an increasing erythrocyte sedimentation rate and C-reactive protein. Further examinations revealed that multiple organ involvement, such as rash, myocardial hypertrophy, peripheral neuropathy. Diagnoses: Cardiac MR demonstrated hypertrophic cardiomyopathy, myocardial fibrosis and low myocardial T1 value. The patient was eventually diagnosed with Fabry disease through proteomics and genetic testing. Interventions: The treatment is enzyme replacement therapy (ERT). But this patient could not afford ERT and was given only general symptomatic treatment, pregabalin, and a gradual reduction in glucocorticoid. Outcomes: The patient’s symptoms of joint pain and muscle weakness reduced significantly, and ESR and CRP had decreased to normal. Lessons: FD is a rare disease and difficult to diagnose, but rare does not mean invisible. FD may present with signs and symptoms of rheumatic diseases. Rheumatologists should be aware and concerned about this disease.

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“…For example, traditional ERT does not reach the CNS, thus being a real therapeutic option only for non-neurologic diseases or for their non-neurological forms. Despite their limitations, ERTs for Gaucher Disease [16], Fabry Disease [17], Acid Lipase Deficiency [18], Ceroid lipofuscinosis type 2 [19], Niemann-Pick diseases type A/B [20] , α-Mannosidosis [21], and MPS I, II, IV, VI, and VII [22] are, nowadays, a reality and numerous patients have benefited from them over the last decades. Additional clinical trials with novel enzymes and alternative delivery routes are also ongoing [23].…”

Section: Lysosomal Storage Diseasesmentioning

confidence: 99%

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step Towards Understanding and Treating Mucopolysaccharidoses

Carvalho¹,

Santos²,

Moreira³

et al. 2023

Preprint

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Despite extensive research, the links between the accumulation of glycosaminoglycans (GAGs) and the clinical features seen in patients suffering from various forms of Mucopolysaccharidoses (MPSs) have yet to be further elucidated. This is particularly true for the neuropathology of these disorders, even though the neurological symptoms are currently incurable, even in the cases where a dis-ease-specific therapeutic approach does exist. One of the best ways to get insights on the molecular mechanisms driving that pathogenesis is the analysis of patient-derived cells. Yet, not every pa-tient-derived cell holds potential to recapitulate relevant disease features. For the neurodegenerative forms of these diseases in particular, it is challenging to grow neuronal cultures that accurately represent them because of the obvious inability to access live neurons. This scenario changed sig-nificantly since Yamanaka et al. published their protocol for induction of pluripotent stem cells (SC) from adult human fibroblasts. From then on, a series of differentiation protocols to generate neurons from induced pluripotent stem cells (iPSC) was developed and extensively used for disease mod-eling. Currently, human iPSC and iPSC-derived cell models have been generated for several MPS and numerous lessons were learnt from their analysis. Here we review most of those studies, not only listing the currently available MPS iPSC lines and their derived models, but also summarizing how they were generated and the major information different groups have gathered from their analysis. Finally, and taking into account that iPSC generation is a laborious/expensive protocol that holds significant limitations, we also comment on a tempting alternative to establish MPS pa-tient-derived neuronal cells in a much more expedite way by taking advantage of the existence of a population of multipotent SC in human dental pulp, to establish mixed neuronal and glial cultures.

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Fabry disease: Mechanism and therapeutics strategies

Cited by 22 publications

References 123 publications

Curcumin Has Beneficial Effects on Lysosomal Alpha-Galactosidase: Potential Implications for the Cure of Fabry Disease

Curcumin Has Beneficial Effects on Lysosomal Alpha-Galactosidase: Potential Implications for the Cure of Fabry Disease

Case report and literature review: Fabry disease misdiagnosing as polymyalgia rheumatica

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step Towards Understanding and Treating Mucopolysaccharidoses

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