- Email: [email protected]
49 A prospective study of neurological manifestations and other comorbidities in adult type I Gaucher disease
S22
Abstracts / Molecular Genetics and Metabolism 92 (2007) S11–S34
syntase (GS) by 1.5-(butylimino)1,5-dideoxy-D-glucitol results in improvement in hematologic indices and organomegaly of approximately 30% over 3 years. These results provide some hope for patients who are allergic to glucocerebrosidase. More importantly, these results provide an indication that the concept of SRT is one that is worthy of further study. EET relies on extending the in situ half-life of GC by improving its delivery to the lysosome and delaying its degradation. The concept and clinical utility of EET is evolving. Studies in progress will be important to unveiling which mutations in the gene coding for GC result in alteration of protein that can be ‘‘chaperoned’’ and how this might play a role in the complex pathogenesis of Gaucher disease. Finally, gene transfer remains as a possible cure for Gaucher disease. Retroviral mediated ex vivo transfer of the GC gene to hematopoetic cells failed to result in a clinical application mostly due to the inability to sufficiently transduce hematopoetic progenitors. Adeno-associated viral gene transfer in vivo results in lifelong reversal of the enzyme deficiency and signs of disease in mouse models of the disease (5,6). Clinical applications of this approach have not yet been attempted. Approaches to the treatment of the neurodegenerative forms of GD (types 2 and 3) are likely to require all forms of therapy including ERT, SRT, EET and gene transfer and perhaps other approaches, only beginning to be defined. doi:10.1016/j.ymgme.2007.08.051
47 The identification and characterization of glucocerebrosidase activators and inhibitors as potential therapeutic agents for Gaucher disease Daniel Urban a, Wei Zheng a, Ozlem Goker-Alpan b, Ehud Goldin b, Janak Padia a, Jim Inglese a, Aashish Goswami b, Chris Austin a, Ellen Sidransky b, a Cell Biology and Molecular Genetics, National Institutes of Health/National Human Genome Research Institute, Bethesda, Maryland, USA, b Medical Genetics Branch and NIH Chemical Genomics Center, National Human Genome Research Institute, NIH Gaucher disease is caused by an inherited deficiency of the lysosomal enzyme glucocerebrosidase (GC). It has been suggested that chemical chaperones might correct the misfolding of the mutant enzyme and thus restore its function. Using quantitative high-throughput screening (qHTS) of a compound collection of over 60,000 chemicals, we identified 299 inhibitors and 56 activators, with a hit rate of 0.57%. Among these were one structure class of GC activators and three classes of GC inhibitors. Twelve compounds were found to have AC50 values at less than 0.5 lmol concentrations. The best inhibitors included three different structural series. In order to characterize the mechanism of action for these compounds and to determine their selectivity profiles, we performed enzyme kinetic assays using five different hydrolases. We found that both the GC activators and inhibitors identified in our screening were highly selective for GC and not the other enzymes tested, and showed better selectivity than existing GC inhibitors. The identification of these selective compounds confirms the power of qHTS, which may ultimately lead to the development of small molecule drugs that can be tested as therapeutic agents for Gaucher disease. doi:10.1016/j.ymgme.2007.08.052
48 Treat type I Gaucher disease with miglustat—Experience with two patients Sandra Yang a, Cynthia Tifft b, a Children’s National Medical Center, Washington, DC, USA, b Medical Genetics and Metabolism Type 1 Gaucher disease (GD) is a recessive disorder with variable manifestations including hepatosplenomegaly, anemia, thrombocytopenia and bone involvement. Intravenous enzyme replacement therapy (ERT) with imiglucerase has been the standard treatment of symptomatic GD. More recently, substrate reduction therapy (SRT) with miglustat has provided an alternative for patients with mild to moderate GD.
We report our experience with two patients receiving miglustat for 30 and 8 months, respectively. The first patient is a 45-year-old female diagnosed with GD (N370S/N370S) at age 25 with fatigue, hepatosplenomegaly and bruisability but no bone involvement. After 7 years of ERT and difficulty in scheduling infusions due to her active lifestyle she requested a trial of miglustat. Side effects included diarrhea, flatulence, and fine tremor. By 6 months the symptoms had decreased and the tremor had resolved coincident with discontinued use of fluoxetine and decreased caffeine consumption. She experienced a 6.3 kg weight loss. The second patient is a 39-year-old female diagnosed with GD (L444P/ R463C) at age 5 due to splenomegaly and bruising underwent splenectomy at age 11. After 12 years of ERT, venous access became very difficult. She requested a trial of miglustat. After 6 months she had lost 5.6 kg (a result of dieting), and had a few loose stools and mild abdominal discomfort. Both patients showed stable hematologic profiles and GD biomarkers. Liver/spleen volume(s) have remained stable. Based on this limited experience we conclude that miglustat is a well-tolerated maintenance therapy for patients with mild to moderate GD. doi:10.1016/j.ymgme.2007.08.053
49 A prospective study of neurological manifestations and other comorbidities in adult type I Gaucher disease C.E.M. Hollak a, L. Marodi b, M. Biegstraaten c, I.N. Van Schaik c, C. Niederau d, D. Hughes e, P. Giraldo f, M. Beck g, a Academic Medical Centre, Amsterdam, North Holland, The Netherlands, b University of Debrecen, Debrecen, Hungary, c Academic Medical Centre, Amsterdam, The Netherlands, d Klinik fur Innere Medizin, Universitat Essen, Duesseldorf, Germany, e Royal Free Hospital, London, UK, f Miguel Servet University Hospital, Zaragoza, Spain, g Universitaets Kinderklinik, Mainz, Germany Gaucher disease (GD) is a complex disorder and comprehensive information on its natural history is relatively limited. Central and peripheral nervous symptoms have been reported as secondary manifestations of type 1 Gaucher disease (GD1). To further investigate these findings, a multinational (5 countries, 6 centres) prospective study has been set up and is currently ongoing with the endorsement of the European Working Group on Gaucher Disease (EWGGD). The objective of this study is to determine the occurrence of neurological symptoms in GD1. The primary endpoints are the prevalence and incidence of peripheral neuropathy (PN) in GD1 patients who have not received miglustat (ZavescaÒ). PN will be confirmed based on consistent signs, symptoms and electrodiagnostic assessments validated by an independent central assessor. Secondary endpoints are incidence of peripheral neuropathies over 2 years, and change from baseline in various clinical and biological parameters such as neurological and neuropsychological status, skeletal symptoms, plasma electrophoresis and quality of life. Descriptive statistics will be used for data analysis. This study will recruit up to 100 patients with GD1, either untreated or treated by enzyme replacement therapy. As of April 2006, 74 patients have been enrolled. This first set of analyses will provide information on the natural history of GD1, with a special focus on the prevalence of peripheral and central neurological manifestations. The comprehensive information provided by this study will contribute towards a better understanding and management of this disease. doi:10.1016/j.ymgme.2007.08.054
50 ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity Mia Horowitz a, Idit Ron b, Adi Ben-Ari b, a Tel Aviv University, Ramat Aviv, Israel, b Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv, Israel Gaucher disease (GD) is characterized by accumulation of glucosylceramide mainly in cells of the reticuloendothelial system, due to mutations in
Abstracts / Molecular Genetics and Metabolism 92 (2007) S11–S34
syntase (GS) by 1.5-(butylimino)1,5-dideoxy-D-glucitol results in improvement in hematologic indices and organomegaly of approximately 30% over 3 years. These results provide some hope for patients who are allergic to glucocerebrosidase. More importantly, these results provide an indication that the concept of SRT is one that is worthy of further study. EET relies on extending the in situ half-life of GC by improving its delivery to the lysosome and delaying its degradation. The concept and clinical utility of EET is evolving. Studies in progress will be important to unveiling which mutations in the gene coding for GC result in alteration of protein that can be ‘‘chaperoned’’ and how this might play a role in the complex pathogenesis of Gaucher disease. Finally, gene transfer remains as a possible cure for Gaucher disease. Retroviral mediated ex vivo transfer of the GC gene to hematopoetic cells failed to result in a clinical application mostly due to the inability to sufficiently transduce hematopoetic progenitors. Adeno-associated viral gene transfer in vivo results in lifelong reversal of the enzyme deficiency and signs of disease in mouse models of the disease (5,6). Clinical applications of this approach have not yet been attempted. Approaches to the treatment of the neurodegenerative forms of GD (types 2 and 3) are likely to require all forms of therapy including ERT, SRT, EET and gene transfer and perhaps other approaches, only beginning to be defined. doi:10.1016/j.ymgme.2007.08.051
47 The identification and characterization of glucocerebrosidase activators and inhibitors as potential therapeutic agents for Gaucher disease Daniel Urban a, Wei Zheng a, Ozlem Goker-Alpan b, Ehud Goldin b, Janak Padia a, Jim Inglese a, Aashish Goswami b, Chris Austin a, Ellen Sidransky b, a Cell Biology and Molecular Genetics, National Institutes of Health/National Human Genome Research Institute, Bethesda, Maryland, USA, b Medical Genetics Branch and NIH Chemical Genomics Center, National Human Genome Research Institute, NIH Gaucher disease is caused by an inherited deficiency of the lysosomal enzyme glucocerebrosidase (GC). It has been suggested that chemical chaperones might correct the misfolding of the mutant enzyme and thus restore its function. Using quantitative high-throughput screening (qHTS) of a compound collection of over 60,000 chemicals, we identified 299 inhibitors and 56 activators, with a hit rate of 0.57%. Among these were one structure class of GC activators and three classes of GC inhibitors. Twelve compounds were found to have AC50 values at less than 0.5 lmol concentrations. The best inhibitors included three different structural series. In order to characterize the mechanism of action for these compounds and to determine their selectivity profiles, we performed enzyme kinetic assays using five different hydrolases. We found that both the GC activators and inhibitors identified in our screening were highly selective for GC and not the other enzymes tested, and showed better selectivity than existing GC inhibitors. The identification of these selective compounds confirms the power of qHTS, which may ultimately lead to the development of small molecule drugs that can be tested as therapeutic agents for Gaucher disease. doi:10.1016/j.ymgme.2007.08.052
48 Treat type I Gaucher disease with miglustat—Experience with two patients Sandra Yang a, Cynthia Tifft b, a Children’s National Medical Center, Washington, DC, USA, b Medical Genetics and Metabolism Type 1 Gaucher disease (GD) is a recessive disorder with variable manifestations including hepatosplenomegaly, anemia, thrombocytopenia and bone involvement. Intravenous enzyme replacement therapy (ERT) with imiglucerase has been the standard treatment of symptomatic GD. More recently, substrate reduction therapy (SRT) with miglustat has provided an alternative for patients with mild to moderate GD.
We report our experience with two patients receiving miglustat for 30 and 8 months, respectively. The first patient is a 45-year-old female diagnosed with GD (N370S/N370S) at age 25 with fatigue, hepatosplenomegaly and bruisability but no bone involvement. After 7 years of ERT and difficulty in scheduling infusions due to her active lifestyle she requested a trial of miglustat. Side effects included diarrhea, flatulence, and fine tremor. By 6 months the symptoms had decreased and the tremor had resolved coincident with discontinued use of fluoxetine and decreased caffeine consumption. She experienced a 6.3 kg weight loss. The second patient is a 39-year-old female diagnosed with GD (L444P/ R463C) at age 5 due to splenomegaly and bruising underwent splenectomy at age 11. After 12 years of ERT, venous access became very difficult. She requested a trial of miglustat. After 6 months she had lost 5.6 kg (a result of dieting), and had a few loose stools and mild abdominal discomfort. Both patients showed stable hematologic profiles and GD biomarkers. Liver/spleen volume(s) have remained stable. Based on this limited experience we conclude that miglustat is a well-tolerated maintenance therapy for patients with mild to moderate GD. doi:10.1016/j.ymgme.2007.08.053
49 A prospective study of neurological manifestations and other comorbidities in adult type I Gaucher disease C.E.M. Hollak a, L. Marodi b, M. Biegstraaten c, I.N. Van Schaik c, C. Niederau d, D. Hughes e, P. Giraldo f, M. Beck g, a Academic Medical Centre, Amsterdam, North Holland, The Netherlands, b University of Debrecen, Debrecen, Hungary, c Academic Medical Centre, Amsterdam, The Netherlands, d Klinik fur Innere Medizin, Universitat Essen, Duesseldorf, Germany, e Royal Free Hospital, London, UK, f Miguel Servet University Hospital, Zaragoza, Spain, g Universitaets Kinderklinik, Mainz, Germany Gaucher disease (GD) is a complex disorder and comprehensive information on its natural history is relatively limited. Central and peripheral nervous symptoms have been reported as secondary manifestations of type 1 Gaucher disease (GD1). To further investigate these findings, a multinational (5 countries, 6 centres) prospective study has been set up and is currently ongoing with the endorsement of the European Working Group on Gaucher Disease (EWGGD). The objective of this study is to determine the occurrence of neurological symptoms in GD1. The primary endpoints are the prevalence and incidence of peripheral neuropathy (PN) in GD1 patients who have not received miglustat (ZavescaÒ). PN will be confirmed based on consistent signs, symptoms and electrodiagnostic assessments validated by an independent central assessor. Secondary endpoints are incidence of peripheral neuropathies over 2 years, and change from baseline in various clinical and biological parameters such as neurological and neuropsychological status, skeletal symptoms, plasma electrophoresis and quality of life. Descriptive statistics will be used for data analysis. This study will recruit up to 100 patients with GD1, either untreated or treated by enzyme replacement therapy. As of April 2006, 74 patients have been enrolled. This first set of analyses will provide information on the natural history of GD1, with a special focus on the prevalence of peripheral and central neurological manifestations. The comprehensive information provided by this study will contribute towards a better understanding and management of this disease. doi:10.1016/j.ymgme.2007.08.054
50 ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity Mia Horowitz a, Idit Ron b, Adi Ben-Ari b, a Tel Aviv University, Ramat Aviv, Israel, b Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv, Israel Gaucher disease (GD) is characterized by accumulation of glucosylceramide mainly in cells of the reticuloendothelial system, due to mutations in