Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease

Ashe, Karen M.; Budman, Eva; Bangari, Dinesh S.; Siegel, Craig; Nietupski, Jennifer B.; Wang, Bing; Desnick, Robert J.; Scheule, Ronald K.; Leonard, John P.; Cheng, Seng H.; Marshall, John

doi:10.2119/molmed.2015.00088

Cited by 75 publications

(73 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Their combination with ERT could further increase therapeutic effects [42], this assumption needs to be confirmed in clinical studies. Furthermore, enhanced uptake of α-gal A into target cells [43] and substrate reduction therapy [44] have been tested in mouse model experiments and can possibly be implemented in human studies in the future, especially in combination with ERT.…”

Section: Discussionmentioning

confidence: 99%

Disease Progression Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult Patients with the Classic Phenotype of Fabry Disease

Nowak¹,

Koch²,

Huynh‐Do³

et al. 2017

Kidney Blood Press Res

View full text Add to dashboard Cite

Background/Aims: Fabry disease (FD) is a rare inherited lysosomal storage disease with common and serious kidney complications. Enzyme replacement therapies (ERT) with agalsidase-α and -β were investigated to characterize their therapeutic effect on kidney function in FD patients with Classic phenotype. Methods: The prospective FD cohort consisted of 98 genetically confirmed patients (females, n = 61, males, n = 37). The median [interquartile range] follow-up time (time difference from first to last visit) was 9 [6, 12] years. The median age of ERT start was 36 [21 – 54] years for females and 39 [28 – 49] years for males. Results: A disease progression model was developed to (i) characterize the time course of estimated glomerular filtration rate (eGFR) and (ii) evaluate therapeutic effects of ERT on kidney function. Change in eGFR over time was best described by the linear model. Females had stable kidney function with and without ERT (eGFR slopes of -0.07 ml/min/1.73m^2 per year and 0.52 ml/min/1.73m^2 per year, respectively). Males with ERT showed an eGFR decrease of -3.07 ml/min/1.73m^2 per year. Conclusion: Mathematical disease progression modeling indicates that there is no clear therapeutic effect of ERT on kidney function in adult patients with Classic Phenotype of FD. Interpretation of these findings should take into account that the study is not randomized and lacks a placebo controlled group. Further investigations are warranted to clarify whether earlier ERT initiation before 18 years of age, higher ERT dose or more intensive therapies can preserve kidney function.

show abstract

Section: Discussionmentioning

confidence: 99%

Disease Progression Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult Patients with the Classic Phenotype of Fabry Disease

Nowak¹,

Koch²,

Huynh‐Do³

et al. 2017

Kidney Blood Press Res

View full text Add to dashboard Cite

show abstract

“…Treating Fabry mice with compound Genz-682452 resulted in reduced tissue substrate and a delayed onset of a deficit in thermosensory responses. The effects were most notable in young mice prior to the development of pathology [48]. These products are not yet approved and remain investigational.…”

Section: Emerging Therapiesmentioning

confidence: 99%

Fabry disease

Hughes

2016

Current Opinion in Cardiology

View full text Add to dashboard Cite

show abstract

“…Similarly, in Fabry mice, GCS inhibitors reduce tissue Gb3 by inhibiting production of the metabolic precursor glucosylceramide (GlcCer) (Fig. 1) (20,32,33). In Fabry mice, GCS inhibitors and ERT have complementary pharmacodynamic profiles, with GCS inhibitors more effectively clearing Gb3 from the kidneys (20,32) .…”

Section: Introductionmentioning

confidence: 99%

“…ERT reduces Gb3 in kidneys, heart and skin (15–18), and is particularly effective in clearing the lipid load from endothelial cells (19). However, distal tubular cells (15), smooth muscle (16) and the dorsal root ganglia (20) are more resistant to ERT (20,21). Unfortunately, the formation of neutralizing antibodies (22) is known to diminish the effectiveness of ERT (23–25).…”

Section: Introductionmentioning

confidence: 99%

Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types

Welford

Mühlemann

Garzotti

et al. 2018

Human Molecular Genetics

View full text Add to dashboard Cite

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene coding for α-galactosidase A (α-GalA). The deleterious mutations lead to accumulation of α-GalA substrates, including globotriaosylceramide (Gb3) and globotriaosylsphingosine. Progressive glycolipid storage results in cellular dysfunction, leading to organ damage and clinical disease, i.e. neuropathic pain, impaired renal function and cardiomyopathy. Many Fabry patients are treated by bi-weekly intravenous infusions of replacement enzyme. While the only available oral therapy is an α-GalA chaperone, which is indicated for a limited number of patients with specific ‘amenable’ mutations. Lucerastat is an orally bioavailable inhibitor of glucosylceramide synthase (GCS) that is in late stage clinical development for Fabry disease. Here we investigated the ability of lucerastat to lower Gb3, globotriaosylsphingosine and lysosomal staining in cultured fibroblasts from 15 different Fabry patients. Patients’ cells included 13 different pathogenic variants, with 13 cell lines harboring GLA mutations associated with the classic disease phenotype. Lucerastat dose dependently reduced Gb3 in all cell lines. For 13 cell lines the Gb3 data could be fit to an IC50 curve, giving a median IC50 [interquartile range (IQR)] = 11 μM (8.2–18); the median percent reduction (IQR) in Gb3 was 77% (70–83). Lucerastat treatment also dose dependently reduced LysoTracker Red staining of acidic compartments. Lucerastat’s effects in the cell lines were compared to those with current treatments—agalsidase alfa and migalastat. Consequently, the GCS inhibitor lucerastat provides a viable mechanism to reduce Gb3 accumulation and lysosome volume, suitable for all Fabry patients regardless of genotype.

show abstract

Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease

Cited by 75 publications

References 41 publications

Disease Progression Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult Patients with the Classic Phenotype of Fabry Disease

Disease Progression Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult Patients with the Classic Phenotype of Fabry Disease

Fabry disease

Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types

Contact Info

Product

Resources

About