Fabry disease: A fundamental genetic modifier of cardiac function

Tadevosyan, Artashes

doi:10.1016/j.retram.2016.09.001

Cited by 4 publications

(3 citation statements)

References 62 publications

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“…Over time, accumulation of glycosphingolipids triggers cellular dysfunction and progressive damage in affected tissues such as kidney, heart, and skin. [8][9][10][11] Individuals with Fabry disease present clinically with a spectrum of disease severity that directly correlates with the level of the residual enzyme activity. Individuals with the early-onset or classic phenotype during childhood or adolescence typically have less than 1% of residual a-Gal A activity and often present with symptoms such as angiokeratoma, acroparesthesias, corneal and lenticular opacities, and hypohidrosis.…”

Section: Introductionmentioning

confidence: 99%

“…9,12,13 The cardiac variant of Fabry disease affects 1:50,000 individuals. 8 However, newborn screening assessments have found that the screen positive rate for mutations in the GLA ranges from 1:3,000 to 1:10,000, indicating that Fabry disease might be significantly underdiagnosed. [14][15][16] Currently there are several commercially available treatments for Fabry disease including enzyme replacement therapies (ERTs) such as Fabrazyme (Genzyme Sanofi) and Replagal (Shire) as well as a small molecule chaperone therapy (CT) such as Galafold (Amicus Therapeutics).…”

Section: Introductionmentioning

confidence: 99%

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Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates

Zhu

Yin

Theisen

et al. 2019

The American Journal of Human Genetics

124

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Fabry disease is an X-linked lysosomal storage disease caused by loss of alpha galactosidase A (a-Gal A) activity and is characterized by progressive accumulation of globotriaosylceramide and its analogs in all cells and tissues. Although enzyme replacement therapy (ERT) is considered standard of care, the long-term effects of ERT on renal and cardiac manifestations remain uncertain and thus novel therapies are desirable. We herein report preclinical studies evaluating systemic messenger RNA (mRNA) encoding human a-Gal A in wild-type (WT) mice, a-Gal A-deficient mice, and WT non-human primates (NHPs). The pharmacokinetics and distribution of h-a-Gal A mRNA encoded protein in WT mice demonstrated prolonged half-lives of a-Gal A in tissues and plasma. Single intravenous administration of h-a-Gal A mRNA to Gla-deficient mice showed dose-dependent protein activity and substrate reduction. Moreover, long duration (up to 6 weeks) of substrate reductions in tissues and plasma were observed after a single injection. Furthermore, repeat i.v. administration of h-a-Gal A mRNA showed a sustained pharmacodynamic response and efficacy in Fabry mice model. Lastly, multiple administrations to non-human primates confirmed safety and translatability. Taken together, these studies across species demonstrate preclinical proof-of-concept of systemic mRNA therapy for the treatment of Fabry disease and this approach may be useful for other lysosomal storage disorders.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates

Zhu

Yin

Theisen

et al. 2019

The American Journal of Human Genetics

124

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“…Fabry disease (FD) is a progressive, X‐linked inherited lysosomal storage disorder caused by genetic variants in the α‐galactosidase A gene ( GLA ) . Partial or complete deficiency of the enzyme α‐galactosidase A (α‐Gal A) results in a progressive accumulation of lipids with terminal α‐galactosyl residues, primarily globotriaosylceramide (Gb3, GL‐3) and its deacylated derivative lyso‐GL‐3 (lyso‐Gb3) and leads to organ damage .…”

Section: Introductionmentioning

confidence: 99%

Diagnostic strategy for females suspected of Fabry disease

Balendran

Oliva²,

Sansen

et al. 2020

Clinical Genetics

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A total of 11 948 females suspicious of Fabry disease were tested by a combined biochemical and genetic approach. The enzyme activity, together with the concentration of lyso‐GL‐3 (lyso‐Gb3) biomarker in dried blood spots (DBS), substantially improved the diagnostic detection of Fabry disease in females compared to the enzyme activity alone. Abnormal values for both were highly suspicious of Fabry disease (97% positive predictive value [PPV], similar to PPV in males). In cases with one abnormal biochemical value, elevated lyso‐GL‐3 is a far more important indicator than low enzyme activity (39% PPV vs 6% PPV). Cases with clearly negative results for both biochemical parameters are unlikely to have Fabry disease, even in clinically highly suspicious cases.

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Genetic disruption of multiple α1,2-mannosidases generates mammalian cells producing recombinant proteins with high-mannose–type N-glycans

Jin

Kitajima

Dong

et al. 2018

Journal of Biological Chemistry

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Recombinant therapeutic proteins are becoming very important pharmaceutical agents for treating intractable diseases. Most biopharmaceutical proteins are produced in mammalian cells because this ensures correct folding and glycosylation for protein stability and function. However, protein production in mammalian cells has several drawbacks, including heterogeneity of glycans attached to the produced protein. In this study, we established cell lines with high-mannose-type -linked, low-complexity glycans. We first knocked out two genes encoding Golgi mannosidases ( and ) in HEK293 cells. Single knockout (KO) cells did not exhibit changes in-glycan structures, whereas double KO cells displayed increased high-mannose-type and decreased complex-type glycans. In our effort to eliminate the remaining complex-type glycans, we found that knocking out a gene encoding the endoplasmic reticulum mannosidase I () in the double KO cells reduced most of the complex-type glycans. In triple KO (, , and) cells, Man9GlcNAc2 and Man8GlcNAc2 were the major -glycan structures. Therefore, we expressed two lysosomal enzymes, α-galactosidase-A and lysosomal acid lipase, in the triple KO cells and found that the glycans on these enzymes were sensitive to endoglycosidase H treatment. The-glycan structures on recombinant proteins expressed in triple KO cells were simplified and changed from complex types to high-mannose types at the protein level. Our results indicate that the triple KO HEK293 cells are suitable for producing recombinant proteins, including lysosomal enzymes with high-mannose-type -glycans.

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Fabry disease: A fundamental genetic modifier of cardiac function

Cited by 4 publications

References 62 publications

Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates

Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates

Diagnostic strategy for females suspected of Fabry disease

Genetic disruption of multiple α1,2-mannosidases generates mammalian cells producing recombinant proteins with high-mannose–type N-glycans

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