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Mucopolysaccharidosis Type VII (Sly disease) survivors
S20
Abstracts
Pair 3: Both (18 and 23 years) recently diagnosed with NPC and started treatment. Onset of neurological symptoms at age 8 and in adolescence. Pair 4: L.M. died at age 5 months due to liver failure. P.M. (7 years): earlyinfantile form, despite treatment start at age 2 progressive neurological deterioration. Pair 5: R.K.: late-infantile form, untreated, died at age 9 due to progressive neurological involvement. M.K.: late infantileform, start of treatment at age 5, died at age 13 due to epileptic encephalopathy. These cases reveal that disease onset and progression in siblings with NPC vary, and that miglustat can slow disease progression. doi:10.1016/j.ymgme.2012.11.023
10 Mucopolysaccharidosis Type VII (Sly disease) survivors Laila Arasha, Nesrin Karabulb, Catharina Whybrab, Christoph Kampmannb, Michael Beckb, Eugen Mengelb, aJohannes Gutenberg University Medicine Mainz, Center for Children and Adolescent Medicine, Mainz, Rheinland-Pfalz, Germany, bVilla Metabolica at the Johannes Gutenberg University Medicine Mainz, Center for Children and Adolescent Medicine, Mainz,Germany Introduction: MPS VII is an ultra-rare, autosomal-recessive lysosomal storage disorder. Deficiency of alpha-glucuronidase based on mutations in the GUSB gene on chromosomal locus 7q21.1–q22 leading to accumulation of chondroitin sulfate in several organs. The most severe and probably the most frequent form of clinical manifestation of MPS VII is hydrops fetalis. Patients with hydrops fetalis die frequently in utero early in the third trimester and rarely survive birth or the newborn period. The clinical presentation of survivors is variable. Unique findings are dysostosis multiplex, hepatosplenomegaly, and mental retardation. Results: In the last 20 years, we diagnosed 10 patients with MPS VII. All patients presented with hydrops fetalis. Three patients survived hydrops fetalis and the newborn period. The first patient, a 15-year-old boy, developed bilateral femual head necrosis and mental retardation followed by cognitive decline resembling Sanfilippo syndrome. The second patient, a 7-year-old girl, showed mental retardation, dysostosis multiplex, hearing loss, mild coarse facial features, umbilical hernia, and hepatosplenomegaly. The third patient was a 9-month-old who and suffered from early manifestations of spinal stenosis resulting in hydrocephalus, respiratory distress and inguinal hernia. Conclusion: Multisystemic signs and symptoms demonstrate that, even in attenuated phenotypes, severe disease burden is seen. MPS VII occurs with an incidence of less than 1:1,000,000. Improvement of pre- and perinatally medical care and diagnosis will probably result in an increased rate of MPS VII diagnosis. So called ‘survivors’ will need continuous monitoring of the disease and symptom related treatment. Enzyme replacement therapy would be a treatment option for these patients. doi:10.1016/j.ymgme.2012.11.024
11 Maintenance of sleeping beauty transposon-mediated expression of human alpha-L-Iduronidase in mice Elena L. Aronovich, Bryan C. Hall, Jason B. Bell, Perry B. Hackett, University of Minnesota, Minneapolis, MN, USA The Sleeping Beauty (SB) transposon system is a non-viral, integrating vector that is efficacious for gene therapy of murine
mucopolysaccharidosis type I (MPS I). We have demonstrated that SB system can deliver alpha-L-iduronidase (IDUA) levels and sustainability of IDUA enzymatic activity comparable to those observed with retroviral vectors. As a consequence, clinical manifestations of the disease in mice are significantly ameliorated. However, life-long expression of the therapeutic IDUA transgene can be curtailed by shutdown of its transcription, as well as immune responses. We examined the levels of IDUA activity for up to 1 year post-treatment in transposon-injected mice under different combinations of SB transposases and transposons, transcriptional regulatory elements directing expression of the transgene, DNA doses, genetic backgrounds and gender of the mice, and immunosuppression. We have calculated rates of attenuation of IDUA activity over time from repression of transcription due to presumed innate immune responses and from acquired immune responses directed against transgenic IDUA and/or the cells that produce it. Mathematical analysis suggests that there are only a few mechanisms that account for loss of transgene expression regardless of the different conditions of gene transfer and gender of mice. The combination of experimental and mathematical approaches facilitates a better understanding of the triggers of IDUA expression decay and ways to prevent or counteract it. doi:10.1016/j.ymgme.2012.11.025
12 A novel, selective and orally-available glucosylceramide synthase inhibitor for substrate reduction therapy of Fabry disease Karen Ashea, John Marshalla, Eva Budmana, Dinesh Bangaria, Jennifer Nietupskia, Robert Desnickb, Ronald Scheulea, John Leonarda, Seng Chenga, aGenzyme, Framingham, MA, USA, bGenetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA Fabry disease, an X-linked glycosphingolipid storage disorder, is caused by a deficiency of acid alpha-galactosidase A (gal). Resulting progressive accumulation of globotriaosylceramide (GL3) and lysoGL3 leads to kidney, heart, and cerebrovascular disease. Presently, Fabry disease is managed by periodic infusions of recombinant gal (enzyme replacement therapy; ERT). However, the inability of ERT to completely address disease manifestations in the heart and kidney has encouraged the development of alternative therapies. We had previously demonstrated that substrate reduction therapy (SRT) through antagonism of glucosylceramide synthase (GCS) can delay the accumulation of GL3 in a mouse model of Fabry disease. Here, we describe the merits of a novel GCS inhibitor (Genz-682452) with favorable pharmacological properties and safety profile in Fabry mice. Treatment of mice with Fabry disease with Genz-682452 starting at 3 months of age resulted in greater correction of a variety of disease biomarkers than when treatment was initiated in 12month-old mice. Mice administered Genz-682452 exhibited significantly lower tissue levels of GL3 and lyso-GL3 and a delayed progression of a thermal nociceptive response than their untreated counterparts. SRT with Genz-682452, perhaps because it has a different biodistribution profile, was more effective than ERT at reducing the levels of the glycosphingolipids in the kidney, heart and CNS, organs that were not well-served by ERT. Importantly, mice treated by both ERT and SRT showed the greatest response suggesting the therapies are both complementary and additive. These results affirm the potential of SRT as an alternative and potentially adjuvant therapy for Fabry disease. doi:10.1016/j.ymgme.2012.11.026
Abstracts
Pair 3: Both (18 and 23 years) recently diagnosed with NPC and started treatment. Onset of neurological symptoms at age 8 and in adolescence. Pair 4: L.M. died at age 5 months due to liver failure. P.M. (7 years): earlyinfantile form, despite treatment start at age 2 progressive neurological deterioration. Pair 5: R.K.: late-infantile form, untreated, died at age 9 due to progressive neurological involvement. M.K.: late infantileform, start of treatment at age 5, died at age 13 due to epileptic encephalopathy. These cases reveal that disease onset and progression in siblings with NPC vary, and that miglustat can slow disease progression. doi:10.1016/j.ymgme.2012.11.023
10 Mucopolysaccharidosis Type VII (Sly disease) survivors Laila Arasha, Nesrin Karabulb, Catharina Whybrab, Christoph Kampmannb, Michael Beckb, Eugen Mengelb, aJohannes Gutenberg University Medicine Mainz, Center for Children and Adolescent Medicine, Mainz, Rheinland-Pfalz, Germany, bVilla Metabolica at the Johannes Gutenberg University Medicine Mainz, Center for Children and Adolescent Medicine, Mainz,Germany Introduction: MPS VII is an ultra-rare, autosomal-recessive lysosomal storage disorder. Deficiency of alpha-glucuronidase based on mutations in the GUSB gene on chromosomal locus 7q21.1–q22 leading to accumulation of chondroitin sulfate in several organs. The most severe and probably the most frequent form of clinical manifestation of MPS VII is hydrops fetalis. Patients with hydrops fetalis die frequently in utero early in the third trimester and rarely survive birth or the newborn period. The clinical presentation of survivors is variable. Unique findings are dysostosis multiplex, hepatosplenomegaly, and mental retardation. Results: In the last 20 years, we diagnosed 10 patients with MPS VII. All patients presented with hydrops fetalis. Three patients survived hydrops fetalis and the newborn period. The first patient, a 15-year-old boy, developed bilateral femual head necrosis and mental retardation followed by cognitive decline resembling Sanfilippo syndrome. The second patient, a 7-year-old girl, showed mental retardation, dysostosis multiplex, hearing loss, mild coarse facial features, umbilical hernia, and hepatosplenomegaly. The third patient was a 9-month-old who and suffered from early manifestations of spinal stenosis resulting in hydrocephalus, respiratory distress and inguinal hernia. Conclusion: Multisystemic signs and symptoms demonstrate that, even in attenuated phenotypes, severe disease burden is seen. MPS VII occurs with an incidence of less than 1:1,000,000. Improvement of pre- and perinatally medical care and diagnosis will probably result in an increased rate of MPS VII diagnosis. So called ‘survivors’ will need continuous monitoring of the disease and symptom related treatment. Enzyme replacement therapy would be a treatment option for these patients. doi:10.1016/j.ymgme.2012.11.024
11 Maintenance of sleeping beauty transposon-mediated expression of human alpha-L-Iduronidase in mice Elena L. Aronovich, Bryan C. Hall, Jason B. Bell, Perry B. Hackett, University of Minnesota, Minneapolis, MN, USA The Sleeping Beauty (SB) transposon system is a non-viral, integrating vector that is efficacious for gene therapy of murine
mucopolysaccharidosis type I (MPS I). We have demonstrated that SB system can deliver alpha-L-iduronidase (IDUA) levels and sustainability of IDUA enzymatic activity comparable to those observed with retroviral vectors. As a consequence, clinical manifestations of the disease in mice are significantly ameliorated. However, life-long expression of the therapeutic IDUA transgene can be curtailed by shutdown of its transcription, as well as immune responses. We examined the levels of IDUA activity for up to 1 year post-treatment in transposon-injected mice under different combinations of SB transposases and transposons, transcriptional regulatory elements directing expression of the transgene, DNA doses, genetic backgrounds and gender of the mice, and immunosuppression. We have calculated rates of attenuation of IDUA activity over time from repression of transcription due to presumed innate immune responses and from acquired immune responses directed against transgenic IDUA and/or the cells that produce it. Mathematical analysis suggests that there are only a few mechanisms that account for loss of transgene expression regardless of the different conditions of gene transfer and gender of mice. The combination of experimental and mathematical approaches facilitates a better understanding of the triggers of IDUA expression decay and ways to prevent or counteract it. doi:10.1016/j.ymgme.2012.11.025
12 A novel, selective and orally-available glucosylceramide synthase inhibitor for substrate reduction therapy of Fabry disease Karen Ashea, John Marshalla, Eva Budmana, Dinesh Bangaria, Jennifer Nietupskia, Robert Desnickb, Ronald Scheulea, John Leonarda, Seng Chenga, aGenzyme, Framingham, MA, USA, bGenetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA Fabry disease, an X-linked glycosphingolipid storage disorder, is caused by a deficiency of acid alpha-galactosidase A (gal). Resulting progressive accumulation of globotriaosylceramide (GL3) and lysoGL3 leads to kidney, heart, and cerebrovascular disease. Presently, Fabry disease is managed by periodic infusions of recombinant gal (enzyme replacement therapy; ERT). However, the inability of ERT to completely address disease manifestations in the heart and kidney has encouraged the development of alternative therapies. We had previously demonstrated that substrate reduction therapy (SRT) through antagonism of glucosylceramide synthase (GCS) can delay the accumulation of GL3 in a mouse model of Fabry disease. Here, we describe the merits of a novel GCS inhibitor (Genz-682452) with favorable pharmacological properties and safety profile in Fabry mice. Treatment of mice with Fabry disease with Genz-682452 starting at 3 months of age resulted in greater correction of a variety of disease biomarkers than when treatment was initiated in 12month-old mice. Mice administered Genz-682452 exhibited significantly lower tissue levels of GL3 and lyso-GL3 and a delayed progression of a thermal nociceptive response than their untreated counterparts. SRT with Genz-682452, perhaps because it has a different biodistribution profile, was more effective than ERT at reducing the levels of the glycosphingolipids in the kidney, heart and CNS, organs that were not well-served by ERT. Importantly, mice treated by both ERT and SRT showed the greatest response suggesting the therapies are both complementary and additive. These results affirm the potential of SRT as an alternative and potentially adjuvant therapy for Fabry disease. doi:10.1016/j.ymgme.2012.11.026