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At least 19 recordsLinked to original sources

PubMed2006

Stop-codon read-through for patients affected by a lysosomal storage disorder.

Lysosomal storage disorders are a group of inherited diseases that can result in severe and progressive pathology due to a specific lysosomal dysfunction. Current treatment strategies include bone-marrow transplantation, substrate reduction, chemical-chaperone and enzyme-replacement therapy. However, each of these treatments has its limitations. Enhanced stop-codon read-through is a potential alternative or adjunct therapeutic strategy for treating lysosomal-storage-disorder patients. Premature stop-codon mutations have been identified in a large cohort of patients with a lysosomal storage disorder, making stop-codon read-through a possible treatment for this disease. In lysosomal-storage-disorder cells (mucopolysaccharidosis type I, alpha-L-iduronidase deficient), preclinical studies have shown that gentamicin induced the read-through of premature stop codons, resulting in enzyme activity that reduced substrate storage.

Codon, Nonsense↗

PubMed2003

Significance of immune response to enzyme-replacement therapy for patients with a lysosomal storage disorder.

Lysosomal storage disorders are collectively important because they cause significant morbidity and mortality. Patients can present with severe symptoms that include somatic tissue and bone pathology, developmental delay and neurological impairment. Enzyme-replacement therapy has been developed as a treatment strategy for patients with a lysosomal storage disorder, and for many of these disorders this treatment is either in clinical trial or clinical practice. One major complication arising from enzyme infusion into patients with a lysosomal storage disorder is an immune response to the replacement protein. From clinical trials, it is clear that there is considerable variability in the level of immune response to enzyme-replacement therapy, dependent upon the replacement protein being infused and the individual patient. Hypersensitivity reactions, neutralizing antibodies to the replacement protein and altered enzyme targeting or turnover are potential concerns for patients exhibiting an immune response to enzyme-replacement therapy. The relative occurrence and significance of these issues have been appraised.

Animals↗

PubMed2003

Mass spectrometry in the study of lysosomal storage disorders.

Lysosomal storage disorders represent a group of over 45 distinct genetic diseases, each one resulting from a deficiency of a particular lysosomal protein or, in a few cases, from non-lysosomal proteins that are involved in lysosomal biogenesis. A common biochemical feature of this group of disorders is the accumulation within lysosomes of undegraded or partially degraded substrates that are normally degraded within, and transported out of the lysosome. The particular substrates stored and the site(s) of storage vary with disease type and enzyme/protein deficiency. The nature of the substrate can be used to group the disorders into broad categories including the mucopolysaccharidoses, lipidoses, glycogenoses and oligosaccharidoses. These categories show many clinical similarities within groups as well as significant similarities between groups. For most lysosomal storage disorders the relationship between the stored substrates (type, amount and location) and the disease pathology is not well understood. The use of mass spectrometry and in particular tandem mass spectrometry provides a powerful tool for the investigation of stored substrates in this group of disorders. In this review we will describe the use of mass spectrometry for the analysis of stored substrates. We will discuss progress in the field, limitations of current methods, and summarise issues relating to the diagnosis and treatment of some of the more prevalent lysosomal storage disorders.

Glycogen Storage Disease↗

PubMed1998

Cellular pathology of lysosomal storage disorders.

Lysosomal storage disorders are rare, inborn errors of metabolism characterized by intralysosomal accumulation of unmetabolized compounds. The brain is commonly a central focus of the disease process and children and animals affected by these disorders often exhibit progressively severe neurological abnormalities. Although most storage diseases result from loss of activity of a single enzyme responsible for a single catabolic step in a single organelle, the lysosome, the overall features of the resulting disease belies this simple beginning. These are enormously complex disorders with metabolic and functional consequences that go far beyond the lysosome and impact both soma-dendritic and axonal domains of neurons in highly neuron type-specific ways. Cellular pathological changes include growth of ectopic dendrites and new synaptic connections and formation of enlargements in axons far distant from the lysosomal defect. Other storage diseases exhibit neuron death, also occurring in a cell-selective manner. The functional links between known molecular genetic and enzyme defects and changes in neuronal integrity remain largely unknown. Future studies on the biology of lysosomal storage diseases affecting the brain can be anticipated to provide insights not only into these pathogenic mechanisms, but also into the role of lysosomes and related organelles in normal neuron function.

Animals↗

PubMed2006

Lysosomal storage disorders.

Lysosomal storage disorders (LSDs) are genetic defects caused by lysosomal hydrolase deficiencies. These deficiencies lead to substrate accumulation affecting cells, tissues and organs. Detecting abnormal compound excretion and deficient enzymes assist diagnosis of these disorders for treatment and prevention. This mini review summarizes clinical presentations and diagnostic workup of LSDs and updates the new development in the area.

Humans↗

PubMed1995

Gene therapy of lysosomal storage disorders.

Lysosomal storage disorders (LSD) result from deficiencies in enzymes normally implicated in the catabolism of macromolecules inside the lysosome. Many of these enzymes can reach the lysosome after being secreted in the extracellular medium and recaptured by specific cell surface receptors. This has suggested a rationale for therapeutic approaches in LSD, in which the missing enzyme is provided by an external source. Current therapies based on this concept, including the administration of purified enzyme and bone marrow transplantation, have been shown to result in clinical improvements in both animal models and patients. Although considerable difficulties must be surmounted, LSD present a favourable situation for gene therapy. The gene corresponding to the affected enzyme has been identified in most diseases and cDNAs are available. Low and unregulated levels of enzyme activity should be sufficient for correction. Importantly, a variety of gene transfer strategies can be carefully evaluated in animal models.

Animals↗

PubMed1999

Newborn screening for lysosomal storage disorders.

Lysosomal storage disorders (LSD) represent a group of over 40 distinct genetic diseases with a total incidence of approximately 1:7,000 births. Bone marrow transplantation and enzyme replacement therapy are currently in use for the treatment of some disorders and new forms of enzyme and gene replacement therapy are actively being researched. The effectiveness of these therapies, particularly for the LSD involving the central nervous system and bone pathology, will rely heavily upon the early diagnosis and treatment of the disorder, before the onset of irreversible pathology. In the absence of a family history the only practical way to detect these disorders will be by a newborn screening program. One common feature of these disorders is an increase in the number and size of lysosomes within the cell from approximately 1% to as much as 50% of total cellular volume. Associated with this, is a corresponding increase in some lysosomal proteins. We propose that the measurement of one or more of these proteins in blood spots taken from Guthrie cards, will form the basis of a newborn screening program, for the detection of all LSD. We have identified a number of lysosomal proteins as potential markers for LSD. The level of these proteins has been determined in blood spots taken from Guthrie cards and in plasma samples from over 300 LSD affected individuals representing 25 disorders. Based on these results we have proposed a strategy for a newborn screening program involving a two tier system, utilizing time resolved fluorescence immunoquantification of the protein markers in the first tier, followed by tandem mass spectrometry for the determination of stored substrates in the second tier assays.

Antigens, CD↗

PubMed2004

The clinical presentation of lysosomal storage disorders.

Lysosomal storage disorders (LSDs) are present from conception and produce a clinical phenotype that evolves with time. The introduction of new therapies has made early diagnosis a priority. Clues to the clinical diagnosis of a LSD can be found in the tempo of the illness especially if the central nervous system is involved. Loss of a previously acquired skill (regression) is very characteristic of this group of disorders. Other clinical clues can include a dysmorphic appearance or the presence of characteristic skeletal involvement (dysostosis multiplex), but in some disorders such as Pompe disease or Krabbe disease, these do not occur. The approach to diagnosis has to involve "screening" as there can be considerable overlap in clinical presentation (e.g. Gaucher disease and Niemann-Pick B). Both urine and blood testing are necessary and the majority of diagnoses can now be confirmed at a molecular level. Prenatal diagnosis is possible for all.

Adult↗

PubMed2006

Newborn screening for lysosomal storage disorders.

Lysosomal storage disorders (LSD) are chronic progressive diseases that have a devastating impact on the patient and family. Most patients are clinically normal at birth but develop symptoms early in childhood. Despite no curative treatment, a number of therapeutic options are available to improve quality of life. To achieve this, there is a pressing need for newborn screening to identify affected individuals early, before the onset of severe irreversible pathology. We have developed a multiplexed immune-quantification assay of 11 different lysosomal proteins for the identification of individuals with an LSD and evaluated this assay in a retrospective study using blood-spots from; newborns subsequently diagnosed with an LSD (n=19, six different LSD), individuals sampled after diagnosis of an LSD (n=92, 11 different LSD), newborn controls (n=433), and adult controls (n=200). All patients with mucopolysaccharidosis type I (MPS I), MPS II, MPS IIIA, MPS VI, metachromatic leukodystrophy, Niemann-Pick disease type A/B, and multiple sulfatase deficiency could be identified by reduced enzyme levels compared to controls. All mucolipidosis type II/III patients were identified by the elevation of several lysosomal enzymes, above the control range. Most Fabry, Pompe, and Gaucher disease patients were identified from either single protein differences or profiles of multiple protein markers. Newborn screening for multiple LSD is achievable using multiplexed immune-quantification of a panel of lysosomal proteins. With further validation, this method could be readily incorporated into existing screening laboratories and will have a substantial impact on patient management and counseling of families.

Adult↗

PubMed2003

Gene transfer strategies for correction of lysosomal storage disorders.

Lysosomal storage diseases (LSDs) represent a large group of monogenic disorders of metabolism, which affect approximately 1 in 5000 live births. LSDs result from a single or multiple deficiency of specific lysosomal hydrolases, the enzymes responsible for the luminal catabolization of macromolecular substrates. The consequent accumulation of undigested metabolites in lysosomes leads to polysystemic dysfunction, including progressive neurologic deterioration, mental retardation, visceromegaly, blindness, and early death. In general, the residual amount of functional enzyme in lysosomes determines the severity and age at onset of the clinical symptoms, implying that even modest increases in enzyme activity might affect a cure. A key feature on which therapy for LSDs is based is the ability of soluble enzyme precursors to be secreted by one cell type and reinternalize by neighboring cells via receptor-mediated endocytosis and routed to lysosomes, where they function normally. In principle, somatic gene therapy could be the preferred treatment for LSDs if the patient's own cells could be genetically modified in vitro or in vivo to constitutively express high levels of the correcting enzyme and become the source of the enzyme in the patient. Both ex vivo and in vivo gene transfer methods have been experimented with for gene therapy of lysosomal disorders. Several of these methods have proved efficient for the transfer of genetic material into deficient cells in culture and reconstitution of enzyme activity. However, the same methods applied to humans or animal models have been giving inconsistent results, the bases of which are not fully understood. A broader knowledge of disease pathogenesis, facilitated by available, faithful animal models of LSDs, coupled to the development of better gene transfer systems as well as the understanding of vector host interactions will make somatic gene therapy for these devastating and complex diseases the most suitable therapeutic approach.

Animals↗

PubMed1999

Prevalence of lysosomal storage disorders.

CONTEXT: Lysosomal storage disorders represent a group of at least 41 genetically distinct, biochemically related, inherited diseases. Individually, these disorders are considered rare, although high prevalence values have been reported in some populations. These disorders are devastating for individuals and their families and result in considerable use of resources from health care systems; however, the magnitude of the problem is not well defined. To date, no comprehensive study has been performed on the prevalence of these disorders as a group. OBJECTIVE: To determine the prevalence of lysosomal storage disorders individually and as a group in the Australian population. DESIGN: Retrospective case studies. SETTING: Australia, from January 1, 1980, through December 31, 1996. MAIN OUTCOME MEASURE: Enzymatic diagnosis of a lysosomal storage disorder. RESULTS: Twenty-seven different lysosomal storage disorders were diagnosed in 545 individuals. The prevalence ranged from 1 per 57000 live births for Gaucher disease to 1 per 4.2 million live births for sialidosis. Eighteen of 27 disorders had more than 10 diagnosed cases. As a group of disorders, the combined prevalence was 1 per 7700 live births. There was no significant increase in the rate of either clinical diagnoses or prenatal diagnoses of lysosomal storage disorders during the study period. CONCLUSIONS: Individually, lysosomal storage disorders are rare genetic diseases. However, as a group, they are relatively common and represent an important health problem in Australia.

Australia↗

PubMed2006

Immunochemistry of lysosomal storage disorders.

BACKGROUND: Lysosomal storage disorders are a group of genetic diseases, each with a broad spectrum of clinical presentation that ranges from attenuated to severe. The immunochemical analysis of patient samples is aimed at several key aspects of patient management, including early detection of the disorder, prediction of clinical severity, determining the most appropriate therapeutic regimen, and monitoring of patients on therapy. METHODS: In this study, we review the current and emerging technology available to achieve these assessments. RESULTS: Immune assays have direct practical application for the early detection, diagnosis and prognosis of lysosomal storage disorder patients. Multiplexing of these assays may provide a platform to allow newborn screening for multiple lysosomal storage disorders. CONCLUSIONS: We have reviewed the immunochemical techniques available for the analysis of lysosomal storage disorder patient samples and advise that these may be used in conjunction with other technologies for effective patient management.

Biomarkers↗

PubMed1995

[Thin-layer chromatography of urine oligosaccharides in diagnosis of some lysosomal storage disorders].

Inherited lysosomal storage disorders are caused by the deficiency or importantly lowered activity of one of the lysosomal enzymes, leading to the storage in the lysosomes the not degraded high-molecular substrates, among others: mucopolysaccharides, glycolipids, oligosaccharides and glycoproteins. Thin-layer chromatography of urine oligosaccharides allows reliable and fast diagnosis of some lysosomal storage disorders e.g. alpha-mannosidosis, fucosidosis, sialidosis, galactosialidosis, Schindler disease, GM1-gangliosidosis, GM2-gangliosidosis (Sandhoff type), Pompe disease, Salla disease, mucolipidosis II and III. We are presenting a modification of the Humbel and Collart's method of TLC of urine oligosaccharides. The principle of our modification is to introduce of the preliminary desalting step of the urine on the columns containing anionit BioRad AG 1 x 8 and cationit Dowex 50 x 8-200.

Adolescent↗

PubMed1997

Lysosomal biogenesis in lysosomal storage disorders.

Lysosomal biogenesis is an orchestration of the structural and functional elements of the lysosome to form an integrated organelle and involves the synthesis, targeting, functional residence, and turnover of the proteins that comprise the lysosome. We have investigated lysosomal biogenesis during the formation and dissipation of storage vacuoles in two model systems. One involves the formation of sucrosomes in normal skin fibroblasts and the other utilizes storage disorder-affected skin fibroblasts; both of these systems result in an increase in the size and the number of lysosomal vacuoles. Lysosomal proteins, beta-hexosaminidase, alpha-mannosidase, N-acetylgalactosamine-4-sulfatase, acid phosphatase, and the lysosome-associated membrane protein, LAMP-1, were shown to be elevated between 2- and 28-fold above normal during lysosomal storage. Levels of mRNA for the lysosome-associated membrane proteins LAMP-1 and LAMP-2, N-acetylgalactosamine-4-sulfatase, and the 46- and 300-kDa mannose-6-phosphate receptors were also elevated 2- to 8-fold. The up-regulation of protein and mRNA lagged 2-4 days behind the formation of lysosomal storage vacuoles. Correction of storage, in both systems, resulted in the rapid decline of the mRNA to basal levels, with a slower decrease in the levels of lysosomal proteins. Lysosomal biogenesis in storage disorders is shown to be a regulated process which is partially controlled at, or prior to, the level of mRNA. Although lysosomal proteins were differentially regulated, the coordination of these events in lysosomal biogenesis would suggest that a common mechanism(s) may be in operation.

Antibodies, Monoclonal↗

PubMed2001

Gene therapy for lysosomal storage disorders.

The lysosomal storage disorders (LSD) are monogenic inborn errors of metabolism with heterogeneous pathophysiology and clinical manifestations. In the last decades, these disorders have been models for the development of molecular and cellular therapies for inherited metabolic diseases. Studies in preclinical in vitro systems and animal models have allowed the successful development of bone marrow transplantation (BMT) and enzyme replacement therapy (ERT) as therapeutic options for several LSDs. However, BMT is limited by poor donor availability and high morbidity and mortality, and ERT is not a life-long cure. Moreover, the neuropathology present in many LSDs responded poorly, if at all, to these treatments. Therefore, gene therapy is an attractive therapeutic alternative. Gene therapy strategies for LSDs have employed ex vivo gene transduction of cellular targets with subsequent transplantation of the enzymatically corrected cells, or direct in vivo delivery of the viral vectors. Oncoretroviral vectors and more recently adeno associated vectors (AAV) and lentiviral vectors have been extensively tested, with some success. This review summarises the main gene therapy strategies which have been employed or are under development for both non-neurological and neuronopathic LSDs. Some of the in vitro and in vivo preclinical studies presented herein have provided the rationale for a gene therapy clinical trial for Gaucher disease Type I.

Animals↗

PubMed2002

Gene therapy for the lysosomal storage disorders.

The lysosomal storage disorders (LSD) are monogenic inborn errors of metabolism with heterogeneous pathophysiology and clinical manifestations. In recent decades, these disorders have been models for the development of molecular and cellular therapies for inherited metabolic diseases. Studies in preclinical in vitro systems and animal models have established proof-of-concept for the development of bone marrow transplantation (BMT) and enzyme-replacement therapy (ERT) as therapeutic options for several LSDs. BMT is limited by poor donor availability and high morbidity and mortality, and although ERT is a good treatment, it is not a life-long cure. Its high cost remains an impediment for developing countries. While substrate synthesis inhibition therapy is an important idea, its clinical use is far from certain. The neuropathology present in many LSDs has responded poorly to BMT or ERT, which makes gene therapy an attractive therapeutic alternative. Oncoretroviral vectors, and more recently adeno-associated and lentiviral vectors have been tested with some success. This review summarizes the main gene therapy strategies which have been employed or are under development for both non-neurological and neuronopathic LSDs. Some of the in vitro and in vivo preclinical studies presented herein have provided the rationale for gene therapy clinical trials for Gaucher disease Type 1.

Animals↗

PubMed1998

Evaluation of the lysosome-associated membrane protein LAMP-2 as a marker for lysosomal storage disorders.

For many lysosomal storage disorders, presymptomatic detection, before the onset of irreversible pathology, will greatly improve the efficacy of current and proposed therapies. In the absence of a family history, presymptomatic detection can be achieved only by a comprehensive newborn screening program. Recently we reported that the lysosome-associated membrane protein LAMP-1 was increased in the plasma from approximately 70% of individuals with lysosomal storage disorders. Here we report on the evaluation of a second lysosome-associated membrane protein, LAMP-2, as a marker for this group of disorders. The median concentration of LAMP-2 in the plasma of healthy individuals was 1.21 mg/L, fourfold higher than the median LAMP-1 concentration (0.31 mg/L). LAMP-2 was increased in >66% of patients with lysosomal storage disorders, and the increases coincided with increased LAMP-1 concentrations. The reference intervals for LAMP-1 and LAMP-2 in blood spots taken from newborns were 0.20-0.54 mg/L (n = 1600) and 0.95-3.06 mg/L (n = 1600), respectively. A high correlation was observed between the concentrations of LAMP-1 and LAMP-2 in both control and affected individuals. The higher concentrations of LAMP-2, relative to LAMP-1, in plasma make LAMP-2 an attractive marker; however, the final selection will be dependent on the availability of new diagnostic markers and their ability to detect disorders currently not identified by LAMP-2.

Adolescent↗

PubMed2003

Small-molecule therapeutics for the treatment of glycolipid lysosomal storage disorders.

Glycosphingolipid (GSL) lysosomal storage disorders are a small but challenging group of human diseases to treat. Although these disorders appear to be monogenic in origin, where the catalytic activity of enzymes in GSL catabolism is impaired, the clinical presentation and severity of disease are heterogeneous. Present attitudes to treatment demand individual therapeutics designed to match the specific disease-related gene defect; this is an acceptable approach for those diseases with high frequency, but it lacks viability for extremely rare conditions. An alternative therapeutic approach termed 'substrate deprivation' or 'substrate reduction therapy' (SRT) aims to balance cellular GSL biosynthesis with the impairment in catalytic activity seen in lysosomal storage disorders. The development of N-alkylated iminosugars that have inhibitory activity against the first enzyme in the pathway for glucosylating sphingolipid in eukaryotic cells, ceramide-specific glucosyltransferase, offers a generic therapeutic for the treatment of all glucosphingolipidoses. The successful use of N-alkylated iminosugars to establish SRT as an alternative therapeutic strategy has been demonstrated in in vitro, in vivo and in clinical trials for type 1 Gaucher disease. The implications of these studies and the prospects of improvement to the design of iminosugar compounds for treating Gaucher and other GSL lysosomal storage disorders will be discussed.

Animals↗