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Substrate reduction augments the efficacy of enzyme therapy in a mouse model of Fabry disease.

Marshall J, Ashe KM, Bangari D, McEachern K, Chuang WL, Pacheco J, Copeland DP, Desnick RJ, Shayman JA, Scheule RK, Cheng SH - PLoS ONE (2010)

Bottom Line: Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease.Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver.Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response.

View Article: PubMed Central - PubMed

Affiliation: Applied Discovery Research, Genzyme Corporation, Framingham, Massachusetts, USA. john.marshall@genzyme.com

ABSTRACT
Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal). This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT). Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638) was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease.

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Substrate reduction therapy is most effective at delaying the onset of heat-insensitivity in Fabry-Rag mice.Treatments were begun at 3 months of age. Latency in treated Fabry-Rag mice and in an age-matched wild-type control group was measured at 11 months of age; a 3-month old untreated Fabry-Rag cohort was included for comparison. Mice were placed on a 55°C hot-plate and the time for them to respond (latency) recorded. Latency is shown for wild-type mice, Fabry-Rag mice treated with ERT every two months (ERT2), ERT every two months+eliglustat tartrate (ERT2+SRT), ERT every four months+eliglustat tartrate (ERT4+SRT), eliglustat tartrate alone (SRT) and an untreated Fabry-Rag cohort. Data are shown as mean ± SEM (n = 10 mice/time point). Statistical comparisons are to the untreated Fabry-Rag mice at 11 months of age, and were determined using the Graphpad Prism software t test (* = p<0.05; ** = p<0.01; *** = p<0.001).
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pone-0015033-g006: Substrate reduction therapy is most effective at delaying the onset of heat-insensitivity in Fabry-Rag mice.Treatments were begun at 3 months of age. Latency in treated Fabry-Rag mice and in an age-matched wild-type control group was measured at 11 months of age; a 3-month old untreated Fabry-Rag cohort was included for comparison. Mice were placed on a 55°C hot-plate and the time for them to respond (latency) recorded. Latency is shown for wild-type mice, Fabry-Rag mice treated with ERT every two months (ERT2), ERT every two months+eliglustat tartrate (ERT2+SRT), ERT every four months+eliglustat tartrate (ERT4+SRT), eliglustat tartrate alone (SRT) and an untreated Fabry-Rag cohort. Data are shown as mean ± SEM (n = 10 mice/time point). Statistical comparisons are to the untreated Fabry-Rag mice at 11 months of age, and were determined using the Graphpad Prism software t test (* = p<0.05; ** = p<0.01; *** = p<0.001).

Mentions: The effects of the different therapeutic regimes on thermal sensitivity in Fabry-Rag mice were also evaluated using the hot-plate assay (Figure 3). Figure 6 shows that the latency of Fabry-Rag mice at 3 months of age (start of study) to react upon being placed on a hot-plate was already significantly increased relative to that of wild-type mice that were 11 months of age (end of study). Left untreated, the latency of Fabry-Rag mice to react to the hot-plate essentially doubled over the eight months of the experiment. Although this progressive increase in latency in the Fabry-Rag was qualitatively similar to that observed in the Fabry model (Figure 3), it was not as dramatic, and did not approach the latency (60 sec) seen in the immunocompetent Fabry mouse. Consistent with the wild-type result shown in Figure 3, latency in the wild-type mouse cohort was unchanged over this same time frame (data not shown). Fabry-Rag mice treated with ERT alone showed no improvement in response time compared to untreated controls. Mice that received SRT alone or SRT combined with ERT showed similarly reduced response times and were all significantly more sensitive to the heat stimulus than untreated Fabry-Rag controls. Taken together, these data suggest that SRT is more effective than ERT at delaying the loss of heat sensitivity in the Fabry-Rag mouse and may therefore provide benefit in treating the peripheral nervous system related symptoms of Fabry patients.


Substrate reduction augments the efficacy of enzyme therapy in a mouse model of Fabry disease.

Marshall J, Ashe KM, Bangari D, McEachern K, Chuang WL, Pacheco J, Copeland DP, Desnick RJ, Shayman JA, Scheule RK, Cheng SH - PLoS ONE (2010)

Substrate reduction therapy is most effective at delaying the onset of heat-insensitivity in Fabry-Rag mice.Treatments were begun at 3 months of age. Latency in treated Fabry-Rag mice and in an age-matched wild-type control group was measured at 11 months of age; a 3-month old untreated Fabry-Rag cohort was included for comparison. Mice were placed on a 55°C hot-plate and the time for them to respond (latency) recorded. Latency is shown for wild-type mice, Fabry-Rag mice treated with ERT every two months (ERT2), ERT every two months+eliglustat tartrate (ERT2+SRT), ERT every four months+eliglustat tartrate (ERT4+SRT), eliglustat tartrate alone (SRT) and an untreated Fabry-Rag cohort. Data are shown as mean ± SEM (n = 10 mice/time point). Statistical comparisons are to the untreated Fabry-Rag mice at 11 months of age, and were determined using the Graphpad Prism software t test (* = p<0.05; ** = p<0.01; *** = p<0.001).
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pone-0015033-g006: Substrate reduction therapy is most effective at delaying the onset of heat-insensitivity in Fabry-Rag mice.Treatments were begun at 3 months of age. Latency in treated Fabry-Rag mice and in an age-matched wild-type control group was measured at 11 months of age; a 3-month old untreated Fabry-Rag cohort was included for comparison. Mice were placed on a 55°C hot-plate and the time for them to respond (latency) recorded. Latency is shown for wild-type mice, Fabry-Rag mice treated with ERT every two months (ERT2), ERT every two months+eliglustat tartrate (ERT2+SRT), ERT every four months+eliglustat tartrate (ERT4+SRT), eliglustat tartrate alone (SRT) and an untreated Fabry-Rag cohort. Data are shown as mean ± SEM (n = 10 mice/time point). Statistical comparisons are to the untreated Fabry-Rag mice at 11 months of age, and were determined using the Graphpad Prism software t test (* = p<0.05; ** = p<0.01; *** = p<0.001).
Mentions: The effects of the different therapeutic regimes on thermal sensitivity in Fabry-Rag mice were also evaluated using the hot-plate assay (Figure 3). Figure 6 shows that the latency of Fabry-Rag mice at 3 months of age (start of study) to react upon being placed on a hot-plate was already significantly increased relative to that of wild-type mice that were 11 months of age (end of study). Left untreated, the latency of Fabry-Rag mice to react to the hot-plate essentially doubled over the eight months of the experiment. Although this progressive increase in latency in the Fabry-Rag was qualitatively similar to that observed in the Fabry model (Figure 3), it was not as dramatic, and did not approach the latency (60 sec) seen in the immunocompetent Fabry mouse. Consistent with the wild-type result shown in Figure 3, latency in the wild-type mouse cohort was unchanged over this same time frame (data not shown). Fabry-Rag mice treated with ERT alone showed no improvement in response time compared to untreated controls. Mice that received SRT alone or SRT combined with ERT showed similarly reduced response times and were all significantly more sensitive to the heat stimulus than untreated Fabry-Rag controls. Taken together, these data suggest that SRT is more effective than ERT at delaying the loss of heat sensitivity in the Fabry-Rag mouse and may therefore provide benefit in treating the peripheral nervous system related symptoms of Fabry patients.

Bottom Line: Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease.Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver.Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response.

View Article: PubMed Central - PubMed

Affiliation: Applied Discovery Research, Genzyme Corporation, Framingham, Massachusetts, USA. john.marshall@genzyme.com

ABSTRACT
Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal). This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT). Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638) was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease.

Show MeSH
Related in: MedlinePlus