Volume 47, No. Suppl 1/2009(Supplement 1)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Foreword
Eighth International Symposium on Lysosomal Storage Diseases
A.B. Mehta, D.P. Germain and R. Martin
Abstract
A.B. Mehta, D.P. Germain and R. Martin
Disease Pathogenesis – Basic Science
Disease pathogenesis – basic science
V. Gieselmann and G. Pintos-Morell
Abstract
V. Gieselmann and G. Pintos-Morell
Disease Pathogenesis – Basic Science
The endosomal network
D.A. Brooks
Abstract
D.A. Brooks1,2
1Molecular Medicine Sector, Sansom Institute, School of Pharmacy and Medical Science, University of South Australia, and 2Lysosomal Diseases Research Unit, Children, Youth and Women’s Health Service, North Adelaide, Australia
Endocytosis is the process by which extracellular molecules are captured by the cell surface membrane and then taken up into the cell. Once inside the cell, the internalized material is delivered to its final destination via a complex system of organelles, termed the endosomal network. These heterogeneous structures play a key role in the delivery of extracellular and cellular material towards the lysosome for macromolecular degradation. The internalization of mannose-6-phosphate receptors at the cell surface, and their subsequent delivery to the late endosome, is the basis of enzyme replacement therapy in patients with lysosomal storage diseases (LSDs). This review describes the characteristics of the endosomal network and discusses how disturbances in vesicular trafficking or intracellular signaling may be important in the pathology of LSDs.Correspondence to:
Prof. D.A. Brooks
Molecular Medicine Sector, Sansom Institute
School of Pharmacy and Medical Science
University of South Australia
GPO Box 2471
Adelaide, SA 5001, Australia
Email: doug.brooks@unisa.edu.au
Disease Pathogenesis – Basic Science
Intracellular trafficking of lysosomal proteins and lysosomes
A. Hasilik, C. Wrocklage and B. Schröder
Abstract
A. Hasilik1, C. Wrocklage1 and B. Schröder2
1Institut für Physiologische Chemie, Philipps-Universität Marburg, Marburg and 2Biochemisches Institut, Universität Kiel, Kiel, Germany
In the synthesis and trafficking of precursors of most lysosomal matrix proteins, the stages necessary for lysosomal delivery include the addition of phosphorylated mannose-rich oligosaccharides, binding of the modified proteins to receptors, their segregation from the secretory pathways and delivery to the endosomal pathway. Targeting of both internally synthesized and externally provided enzymes (as in enzyme replacement therapy) to endosomes is executed by a complex machinery of membrane and cytosolic proteins. Recently, the homotypic fusion and vacuolar protein sorting (HOPS) complex has been identified in lysosomes from human cells. This complex is likely to play an important role in the exchange of enzymes between endosomal and lysosomal compartments. The present review describes the interactions and functions of proteins that participate in delivering lysosomal proteins to different lysosomal compartments. In summary, lysosomal trafficking depends on the recognition of many structural signals. It delivers soluble and membrane proteins, and can be exploited for therapeutic substitution of missing enzymes.Correspondence to:
Prof. A. Hasilik
Institut für Physiologische Chemie
Philipps-Universität Marburg
Karl-von-Frisch-Str. 1
35032 Marburg, Germany
Email: hasilik@staff.uni-marburg.de
Disease Pathogenesis – Basic Science
Disease pathogenesis explained by basic science: lysosomal storage diseases as autophagocytic disorders
A. Ballabio
Abstract
A. Ballabio
Telethon Institute of Genetics and Medicine (TIGEM), Napoli, Italy
Lysosomal storage diseases (LSDs) are characterized by intra-lysosomal accumulation of undegraded metabolites due to the defective activity of lysosomal enzymes. There is a paucity of data, however, relating to the mechanisms that link this accumulation with disease pathology. Several LSDs can be attributed to deficiencies in the activity of sulfatase enzymes. The gene responsible for the post-translational modification that activates sulfatases, sulfatase modifying factor 1 (SUMF1), is defective in the rare autosomal recessive disorder multiple sulfatase deficiency (MSD). A mouse model of MSD (Sumf1 knockout mouse) exhibits a similar phenotype to patients with MSD, with marked lysosomal storage of undegraded metabolites, and increased expression of inflammatory markers and apoptotic markers. Investigation of disease pathology in mouse models of two LSDs (MSD and mucopolysaccharidosis (MPS) Type IIIA) has revealed an increased number of autophagosomes in these animals compared with wild-type mice. This appears to result from impaired autophagosome-lysosome fusion, which may in turn lead to an absence of autophagy. The suggestion that LSDs can be defined as disorders of autophagy implies that there may be some overlap between pathological mechanisms of LSDs and more common neurodegenerative diseases, and this may help provide direction for future therapeutic strategies.Correspondence to:
Prof. A. Ballabio
Professor of Medical Genetics
Director Telethon Institute of Genetics and Medicine (TIGEM)
Via Pietro Castellino 111
80131 Napoli, Italy
Email: ballabio@tigem.it
Disease Pathogenesis – Clinical Interpretation
Disease pathogenesis – clinical interpretation
J. Hopwood and R. Ebner
Abstract
J. Hopwood and R. Ebner
Disease Pathogenesis – Clinical Interpretation
Autophagy in skeletal muscle: implications for Pompe disease
L. Shea and N. Raben
Abstract
L. Shea and N. Raben
The Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
Pompe disease is caused by an inherited deficiency of acid a-glucosidase (GAA), a lysosomal enzyme that catalyzes the breakdown of glycogen to glucose. In the absence of GAA, enlarged, glycogen-laden lysosomes accumulate in multiple tissues, although the major clinical manifestations are seen in cardiac and skeletal muscle. For many years, it was believed that the rupture of glycogen-filled lysosomes was the major cause of the profound muscle damage observed in patients with Pompe disease. Here, we present evidence that a failure of productive autophagy in muscle tissue contributes strongly to disease pathology in both patients with Pompe disease and GAA-knockout mice. In the GAA-knockout mouse model, progressive accumulation of autophagic vesicles is restricted to Type II-rich muscle fibers. Not only does this build-up of autophagosomes disrupt the contractile apparatus in the muscle fibers, it also interferes with enzyme replacement therapy by acting as a sink for the recombinant enzyme and preventing its efficient delivery to the lysosomes. Our data indicate that a re-examination of the presumed pathological mechanism in Pompe disease is necessary, and suggest that successful treatment of patients with Pompe disease will require consideration of the dramatic failure of autophagy that occurs in this disease.Correspondence to:
Dr. N. Raben
50 South Drive, 9000 Rockville Pike
Bld 50, Room 1345
NIAMS, NIH, Bethesda, MD 20892-1820, USA
Email: rabenn@arb.niams.nih.gov
Disease Pathogenesis – Clinical Interpretation
The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease
E.H. Schuchman
Abstract
E.H. Schuchman
Department of Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA
Patients with Niemann-Pick disease (NPD) Types A and B have an inherited deficiency of acid sphingomyelinase (ASM) activity. The clinical spectrum of this disorder ranges from the infantile neurological form that results in death by 3 years of age (NPD Type A) to the non-neurological form that is compatible with survival into adulthood (NPD Type B). Intermediate cases have also been reported, and the disease is best thought of as a single entity with a spectrum of phenotypes. ASM deficiency is panethnic, but appears to be more frequent in individuals of Middle Eastern and North African descent. Current estimates of the disease incidence range from 0.5 to 1 per 100,000 births, although these approximations are thought to underestimate the true frequency of the disorder. The gene encoding ASM – SMPD1 – has been studied extensively, and over 100 mutations in SMPD1 have been found to cause ASM-deficient NPD. Based on these findings, DNA-based carrier screening has been implemented in the Ashkenazi Jewish community. ASM-knockout mouse models also have been generated and used to investigate disease pathogenesis and treatment with stem cell transplantation, gene therapy and enzyme replacement therapy (ERT). Based on these studies, clinical trials of ERT are underway in patients with non-neurological ASM-deficient NPD.Correspondence to:
Prof. E.H. Schuchman
Genetic Disease Foundation – Francis Crick
Professor, Vice Chairman for Research
Department of Genetics & Genomic Sciences
Mount Sinai School of Medicine
1425 Madison Avenue, Room 14-20A
New York, NY 10029, USA
Email: edward.schuchman@mssm.edu
Current State of the Management of LSDs
Current state of the management of LSDs
D.P. Germain and M. Aggio
Abstract
D.P. Germain and M. Aggio
Current State of the Management of LSDs
Enzyme replacement therapy for the management of the mucopolysaccharidoses
J.E. Wraith
Abstract
J.E. Wraith
Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Manchester, UK
Enzyme replacement therapy (ERT) is now available for several of the mucopolysaccharidosis disorders. This brief review summarizes the role of ERT in reducing the burden of peripheral disease in many patients with mucopolysaccharidosis disorders, and describes the challenges that remain in treating the neurological manifestations of these conditions.Correspondence to:
Dr. J.E. Wraith
Willink Biochemical Genetics Unit
Royal Manchester Children’s Hospital
Hospital Road, Manchester M27 4HA, UK
Email: ed.wraith@cmmc.nhs.uk
Current State of the Management of LSDs
Anderson-Fabry disease: developments in diagnosis and treatment
A.B. Mehta
Abstract
A.B. Mehta
Lysosomal Storage Disorders Unit, Department of Haematology, Royal Free Hospital and University College Medical School, London, UK
Anderson-Fabry disease (commonly known as Fabry disease) is an X-linked disorder that is caused by deficiency of the lysosomal enzyme a-galactosidase A. The resulting accumulation of globotriaosylceramide leads to a wide spectrum of clinical signs and symptoms that affect many organs, including the kidneys, heart and brain. In recent years, our understanding of the natural history of Fabry disease has improved considerably, as have methods of clinical characterization and diagnosis. It is now apparent that this disorder may be much more common than previously suspected. The long-term efficacy of enzyme replacement therapy (ERT) in reducing disease burden in patients with Fabry disease continues to be demonstrated in clinical trials and observational studies; however, it is clear that ERT has limitations. This review provides an overview of current issues in the diagnosis and treatment of patients with Fabry disease and considers what may lie ahead in this rapidly evolving therapeutic area.Correspondence to:
Dr. A. Mehta
Department of Haematology
Royal Free Hospital and University College Medical School
Pond Street, London NW3 2QG, UK
Email: atul.mehta@royalfree.nhs.uk
Current State of the Management of LSDs
Krabbe disease: an overview
G.M. Pastores
Abstract
G.M. Pastores
Departments of Neurology and Pediatrics, New York University School of Medicine, New York, NY, USA
Krabbe disease (globoid cell leukodystrophy) is a neurodegenerative disorder that is caused by deficiency of the lysosomal enzyme galactosylceramidase. The resulting accumulation of incompletely metabolized galactocerebroside, which is a component of myelin, leads to progressive white matter disease. The severity of signs and symptoms is partly influenced by the causal mutations and corresponding residual enzyme activity. This review explains how the disease might manifest and discusses methods for diagnosis and staging of the disease process. The current understanding of the mechanisms underlying Krabbe disease is summarized, and therapeutic options – including current and investigational approaches – are outlined.Correspondence to:
Prof. G.M. Pastores
Departments of Neurology and Pediatrics
New York University School of Medicine
403 East 34th Street, New York, NY 10016, USA
Email: gregory.pastores@med.nyu.edu
LSDs and the Immune System
LSDs and the immune system
M. Beck and M. Vanier
Abstract
M. Beck and M. Vanier
LSDs and the Immune System
Perspectives from B cell immunology: fact and fancy
S.V. Hunt
Abstract
S.V. Hunt
Dunn School of Pathology, University of Oxford, Oxford, UK
In this article, the formation of antibodies during enzyme replacement therapy (ERT) for lysosomal storage diseases (LSDs) is reviewed in the light of present-day immunological concepts of immunogenicity and tolerance. Except in Gaucher disease, anti-enzyme antibodies frequently form (mainly immunoglobulin G) in patients receiving ERT, though they tend to wane as treatment continues. If the therapeutic enzyme is inhibited by antibodies, no significant modification to treatment is normally warranted, in clear contrast to therapy of hemophilia with clotting factors. The main adverse consequences of ERT, observed in only some patients, are sporadic hypersensitivity reactions, which are likely to be humorally mediated. Some infusion-related reactions are probably due to antibodies. In order to minimize immunogenicity, infused enzymes should be deaggregated and administered at low doses. In addition, inadvertent exposure to co-stimuli that might activate antigen-specific T or B lymphocytes should be avoided. The presence of cross-reacting immunological material, such as in patients with low levels or missense mutations of a gene coding for a lysosomal enzyme, tends to correlate with immune tolerance to the administered enzyme. There is a need for reliable biomarkers for therapeutic efficacy: some directions for further exploration are suggested. In animal models of LSDs, gene therapy delivered via viral vectors can rectify the lysosomal defect, and regulatory T cells that suppress antibody formation can be induced. This is a promising strategy that warrants further investigation in patients with LSDs.Correspondence to:
Dr. S.V. Hunt
Dunn School of Pathology
South Parks Road
Oxford, OX1 3RE, UK
Email: simon.hunt@path.ox.ac.uk
LSDs and the Immune System
Management of infusion-related reactions to enzyme replacement therapy in a cohort of patients with mucopolysaccharidosis disorders
E. Miebach
Abstract
E. Miebach
Villa Metabolica, Children’s Hospital, University of Mainz, Mainz, Germany
Objective: Enzyme replacement therapy (ERT) is currently available for the treatment of mucopolysaccharidosis (MPS) Type I, MPS II and MPS VI. Hypersensitivity reactions have been reported in some patients receiving ERT, but these can usually be easily managed. Methods: In this retrospective study, we evaluated the manifestations and management of hypersensitivity reactions in patients at a single center who were receiving ERT for either MPS I, MPS II or MPS VI between 2002 and 2008. Results: Hypersensitivity reactions were observed in 28 (36%) out of 77 patients, and were most common in children with severe disease. When an infusion-related reaction occurred, ERT was immediately suspended until the patient’s symptoms had resolved. Antihistamines and antipyretics were administered to treat the acute symptoms of hypersensitivity reactions. In some patients, low-dose corticosteroids were administered to attenuate late-phase or biphasic reactions. There were no instances in which resuscitation was necessary. When ERT was restarted, patients were given premedication in the form of antihistamines and antipyretics, and ERT was administered at a slower rate. In most cases, this approach overcame the hypersensitivity. After gradually increasing the infusion rate, patients were generally able to resume a normal infusion schedule without premedication after a period ranging from 8 weeks to 3.5 years. Conclusion: Close monitoring of patients receiving ERT is essential. Use of an adapted ERT infusion regimen with premedication resulted in improvement of signs and symptoms of hypersensitivity in most of the patients who experienced infusion-related reactions.Correspondence to:
Dr. E. Miebach
Villa Metabolica, Children’s Hospital
University of Mainz, Mainz, Germany
Email: miebach@kinder.klinik.uni-mainz.de
Novel Therapies and Future Perspectives
Novel therapies and future perspectives
M. Scarpa and A. Frustaci
Abstract
M. Scarpa and A. Frustaci
Novel Therapies and Future Perspectives
Pharmacological chaperone therapy by active-site-specific chaperones in Fabry disease: in vitro and preclinical studies
D.P. Germain, and J.-Q. Fan
Abstract
D.P. Germain1,2 and J.-Q. Fan3
1Laboratoire de Génétique et Biologie Cellulaire, Université de Versailles – St Quentin en Yvelines (UVSQ), Versailles, 2Assistance Publique, Centre de Référence de la Maladie de Fabry et des Maladies Héréditaires du Tissu Conjonctif, Unité Fonctionnelle de Génétique Medicale, Hôpital Raymond Poincaré (AP-HP), Garches, France, and 3Pfantastic Medical Research Institute, Cresskill, NJ, USA
Many genetic disorders are due to protein misfolding and excessive premature degradation in the endoplasmic reticulum (ER). When a gene mutation does not affect the functionality of the protein, it may still promote the premature clearance of the protein by ER-associated degradation (ERAD), resulting in a loss of function. Competitive inhibitors are often effective active-site-specific chaperones when used at sub-inhibitory concentrations. Active-site-specific chaperones assist in the folding of mutant lysosomal enzymes in the ER, thereby promoting their escape from ERAD, enhancing trafficking to the lysosome and increasing the level of residual enzyme activity. In Fabry disease, degradation of various mutant forms of a-galactosidase A (alpha-gal A) has been shown to take place in the ER as a result of protein misfolding. One of the most potent inhibitors of alpha-gal A, 1-deoxygalactonojirimycin, has also been shown to be effective in enhancing residual alpha-gal A activity in cultured fibroblasts and lymphoblasts established from patients with Fabry disease caused by a variety of missense mutations. Oral administration of 1-deoxygalactonojirimycin to transgenic mice expressing a mutant form of human alpha-gal A (R301Q) yielded higher alpha-gal A activity in major tissues, compared with untreated transgenic mice.Correspondence to:
Prof. D.P. Germain
Unité Fonctionnelle de Génétique Médicale
Hôpital Raymond Poincaré (AP-HP)
92380 Garches, France
Email: dominique.germain@rpc.aphp.fr
Novel Therapies and Future Perspectives
Delivery of recombinant proteins via the cerebrospinal fluid as a therapy option for neurodegenerative lysosomal storage diseases
K.M. Hemsley and J.J. Hopwood
Abstract
K.M. Hemsley and J.J. Hopwood
Lysosomal Diseases Research Unit, SA Pathology, Women’s and Children’s Hospital campus, North Adelaide, Australia
Patients with lysosomal storage diseases (LSDs) have a greatly diminished lifespan and reduced quality of life, particularly those with neurological manifestations. There are few therapeutic options available to treat the neurological signs and symptoms of LSDs. It is, therefore, imperative that efficacious and tolerable treatments are developed. Hematopoietic stem cell transplantation is carried out in some LSDs in which there is neurological involvement. However, this approach is associated with significant morbidity and mortality, and not all patients who receive this treatment exhibit improvements in cognitive signs and symptoms. A growing body of research in animal models of LSDs appears to support the efficacy of repeated delivery of recombinant lysosomal proteins via injection into the cerebrospinal fluid (CSF). Studies in dogs with mucopolysaccharidosis (MPS) Type 1 have shown that this approach enables widespread distribution of the recombinant protein within the brain, leading to a reduction in LSD pathology. Subsequent studies in MPS IIIA mice revealed that this strategy was also effective in ameliorating neuropathology and improving clinical signs in these animals. More recent studies in mice with Krabbe disease or a late infantile form of neuronal ceroid lipofuscinosis have demonstrated that delivery of recombinant proteins into the CSF may be efficacious in reducing disease pathology and neurological signs and symptoms. Whilst there are still important issues that need to be addressed, such as humoral immune responses to therapeutic protein administration and dose/ frequency selection, this approach represents a medium-term option for treating these devastating conditions. This review summarizes some of the findings and challenges ahead.Correspondence to:
Dr. K.M. Hemsley
Lysosomal Diseases Research Unit
SA Pathology, 4th Floor Rogerson Building
Women’s and Children’s Hospital campus
72 King William Road
North Adelaide, SA 5006, Australia
Email: kim.hemsley@adelaide.edu.au
Novel Therapies and Future Perspectives
Novel treatments and future perspectives: outcomes of intrathecal drug delivery
P.I. Dickson
Abstract
P.I. Dickson
Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
Intrathecal enzyme replacement therapy (ERT) holds promise as a treatment for the central nervous system manifestations of lysosomal storage diseases. Treatment via the cerebrospinal fluid represents a potential method of delivering recombinant enzyme across the blood-brain barrier. Experiments in animal models of mucopolysaccharidosis (MPS) Type I, MPS II and MPS IIIA have shown that ERT delivered via the intrathecal route distributes throughout the central nervous system and penetrates brain tissue, where it promotes clearance of lysosomal storage material. Studies are underway to investigate the safety and efficacy of intrathecal ERT in patients with MPS I.Correspondence to:
Prof. P.I. Dickson
Division of Medical Genetics
LA BioMed at Harbor-UCLA
1124 W. Carson Street, E-4
Torrance, CA 90502, USA
Email: pdickson@ucla.edu
Novel Therapies and Future Perspectives
Gene therapy in metachromatic leukodystrophy
C. Sevin, N. Cartier-Lacave and P. Aubourg
Abstract
C. Sevin, N. Cartier-Lacave and P. Aubourg
French Institute for Health and Medical Research (INSERM), Paris Descartes University and Department of Pediatric Neurology, Hôpital Saint-Vincent de Paul, Paris, France
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by deficiency of the lysosomal enzyme arylsulfatase A. Deficiency of this enzyme results in intralysosomal storage of sphingolipid cerebroside 3-sulfates (sulfatides), which are abundant in myelin and neurons. A pathological hallmark of MLD is demyelination and neurodegeneration, causing various and ultimately lethal neurological symptoms. This review discusses the potential therapeutic application of hematopoietic stem cell gene therapy and intracerebral gene transfer (brain gene therapy) in patients with MLD.Correspondence to:
Prof. P. Aubourg
Department of Pediatric Neurology
Hôpital Saint-Vincent de Paul
82 Avenue Denfert-Rochereau
75014 Paris, France
Email: patrick.aubourg@inserm.fr
Poster Abstracts
Fabry disease
Poster Abstracts
Hunter syndrome
Poster Abstracts
Gaucher disease
Poster Abstracts
Other lysosomal storage diseases
Poster Abstracts
Clinical vignettes
