ORCID Profile
0000-0002-4485-7714
Current Organisations
University of Adelaide
,
Flinders University
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Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.BBR.2008.03.024
Abstract: Mucopolysaccharidosis (MPS) IIIA, or Sanfilippo syndrome, is a lysosomal storage disorder characterized by severe and progressive neuropathology. Following an asymptomatic period, patients may present with sleep disturbances, cognitive decline, aggressive tendencies and hyperactivity. A naturally-occurring mouse model of MPS IIIA also exhibits many of these behavioral features and has been recently back-crossed onto a C57BL/6 genetic background. To more thoroughly characterize the behavioral phenotype of congenic MPS IIIA mice, we assessed exploratory activity and unconditioned anxiety-related behavior in the elevated plus maze (EPM) and open field locomotor activity. Although MPS IIIA male mice were less active in the EPM at 18 and 20 weeks of age, they were more likely to explore the open arms than their normal counter-parts suggesting reduced anxiety. Repeated EPM testing reduced exploration of the open arms in MPS IIIA mice. In the open field test, significant reductions in activity were evident in naïve-tested male MPS IIIA mice from 10 weeks of age. Female normal and MPS IIIA mice displayed similar exploratory activity in the open field test. These differences in anxiety and locomotor activity will allow us to evaluate the efficacy of therapeutic regimes for MPS IIIA as a forerunner to developing safe and effective therapies for Sanfilippo patients.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2017
DOI: 10.1007/S00109-017-1562-0
Abstract: The mucopolysaccharidoses (MPS) are a subgroup of lysosomal storage disorders that are caused by mutations in the genes involved in glycosaminoglycan breakdown. Multiple organs and tissues are affected, including the central nervous system. At present, hematopoietic stem cell transplantation and enzyme replacement therapies are approved for some of the (non-neurological) MPS. Treatments that effectively ameliorate the neurological aspects of the disease are being assessed in clinical trials. This review will focus on the recent outcomes and planned viral vector-mediated gene therapy clinical trials, and the pre-clinical data that supported these studies, for MPS-I (Hurler/Scheie syndrome), MPS-II (Hunter syndrome), and MPS-IIIA and -IIIB (Sanfilippo syndrome).
Publisher: Springer Berlin Heidelberg
Date: 2013
Publisher: Elsevier BV
Date: 06-2022
Publisher: Oxford University Press (OUP)
Date: 27-08-2007
DOI: 10.1093/HMG/DDM223
Abstract: Mucopolysaccharidosis type IIIA (MPS-IIIA or Sanfilippo syndrome) is a lysosomal storage disorder caused by the congenital deficiency of sulfamidase (SGSH) enzyme and consequent accumulation of partially degraded heparan sulfate (HS) in lysosomes. The central nervous system (CNS) is the predominant site of tissue damage in MPS-IIIA. Here we describe a gene therapy approach for MPS-IIIA in a mouse model using recombinant adeno-associated virus serotype 5 (AAV2/5) as a vehicle to deliver therapeutic genes to the CNS. SUMF1 (SUlfatase Modifying Factor 1) exhibits an enhancing effect on sulfatase activity when co-expressed with sulfatases. Consistent with these findings, we demonstrated that co-delivery of SUMF1 and SGSH (via an AAV2/5-CMV-SGSH-IRES-SUMF1 vector) resulted in a synergistic increase in SGSH activity, both in primary neural cells and in murine brain. A study aimed at testing the therapeutic efficacy of simultaneous brain administration of SUMF1 and SGSH was then performed by injecting the lateral ventricles of newborn MPS-IIIA/normal mice with either AAV2/5-CMV-SGSH-IRES-SUMF1 or AAV2/5-CMV-GFP vectors. Widespread GFP expression was observed within the GFP-injected brain, and a stable and significant increase of SGSH activity was detected in several brain regions following SGSH-IRES-SUMF1 administration. Treatment with AAV2/5-CMV-SGSH-IRES-SUMF1 vectors resulted in a visible reduction in lysosomal storage and inflammatory markers in transduced brain regions. Finally, the MPS-IIIA mice treated with therapeutic genes displayed an improvement in both motor and cognitive functions. Our results suggest that early treatment of CNS lesions by AAV-mediated intraventricular injection of both SGSH and SUMF1 genes may represent a feasible therapy for MPS-IIIA.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.NEUROSCIENCE.2019.12.042
Abstract: Lysosomal network dysfunction is a prominent feature of Alzheimer's disease (AD). Although transgenic mouse models of AD are known to model some aspects of lysosomal network dysfunction, the lysosomal network has not yet been examined in the knock-in App
Publisher: Elsevier BV
Date: 02-2004
DOI: 10.1016/J.YMGME.2003.11.007
Abstract: The mucopolysaccharidoses (MPS) are lysosomal storage disorders resulting from the impaired catabolism of glycosaminoglycans (GAG). MPS type IIIA patients have dysfunctional sulfamidase enzyme leading to lysosomal storage of the GAG heparan sulfate, severe neurological symptoms including regression in learning, behavioural abnormalities, and premature death. We have engineered mouse D3 embryonic stem (ES) cells to over-express recombinant human sulfamidase. Human sulfamidase was correctly folded and secreted 2h post-labelling as determined by immunoprecipitation and SDS-PAGE analysis of transfected ES cells. Secreted human sulfamidase present in conditioned ES cell media was able to be taken up via mannose-6-phosphate-mediated endocytosis and restored sulfamidase enzyme activity in human MPS IIIA fibroblast cell lines. ES cells underwent directed differentiation to neural precursor populations and were capable of sustained human sulfamidase over-expression at all stages. Additionally, transfected and control cells were proliferative (Ki67+) and expressed several neural markers (nestin, MAP-2, and NF160) as determined by immunofluorescence. These findings suggest the possibility of ES cell-based therapy for the treatment of neurological pathology of MPS IIIA.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.GENE.2011.09.004
Abstract: Mucopolysaccharidosis type IIIA (MPS-IIIA) is a severe neurodegenerative lysosomal storage disorder caused by a deficiency of N-sulfoglucosamine sulfohydrolase (SGSH) activity with subsequent accumulation of partially-degraded heparan sulfate and other glycolipids. In this study, we have evaluated a gene therapy approach using a helper-dependent canine adenovirus vector that expresses human SGSH as a means of delivering sustained transgene expression to the brain. Initial testing in a mixed neural cell culture model demonstrated that the vector could significantly increase SGSH activity in transduced cells, resulting in near-normalization of heparan sulfate-derived fragments. While administration of vector by direct injection into the brain of adult MPS-IIIA mice enabled transgene expression for at least 8.5 months post-treatment, it was only in discrete areas of brain. Heparan sulfate storage was reduced in some regions following treatment, however there was no improvement in secondary neuropathological changes. These data demonstrate that helper-dependent canine adenovirus vectors are capable of neural transduction and mediate long-term transgene expression, but increased SGSH expression throughout the brain is likely to be required in order to effectively treat all aspects of the MPS-IIIA phenotype.
Publisher: Elsevier BV
Date: 12-2015
Publisher: Elsevier BV
Date: 02-2017
Publisher: Wiley
Date: 23-01-2017
DOI: 10.1111/JNC.13935
Abstract: Alzheimer's disease (AD) is the most common cause of dementia, and its prevalence will increase significantly in the coming decades. Although important progress has been made, fundamental pathogenic mechanisms as well as most hereditary contributions to the sporadic form of the disease remain unknown. In this review, we examine the now substantial links between AD pathogenesis and lysosomal biology. The lysosome hydrolyses and processes cargo delivered by multiple pathways, including endocytosis and autophagy. The endo-lysosomal and autophagic networks are central to clearance of cellular macromolecules, which is important given there is a deficit in clearance of amyloid-β in AD. Numerous studies show prominent lysosomal dysfunction in AD, including perturbed trafficking of lysosomal enzymes and accumulation of the same substrates that accumulate in lysosomal storage disorders. Examination of the brain in lysosomal storage disorders shows the accumulation of amyloid precursor protein metabolites, which further links lysosomal dysfunction with AD. This and other evidence leads us to hypothesise that genetic variation in lysosomal genes modifies the disease course of sporadic AD.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Wiley
Date: 08-03-2018
DOI: 10.1007/S10545-018-0160-9
Abstract: Mucopolysaccharidosis (MPS) type IIIA is an inherited, neurodegenerative lysosomal storage disorder resulting from mutations in the SGSH gene. Consequently, N-sulphoglucosamine sulphohydrolase enzyme activity is reduced resulting in impaired catabolism of heparan sulphate. After an asymptomatic period, patients typically show a progressive loss of cognitive and motor skills, with death often during the second decade of life. The diagnostic criteria of autism spectrum disorders (ASD) include impaired communication and social interactions, as well as displays of repetitive behaviours and fixed interests. Children with MPS-IIIA have been shown to exhibit decreased social communicative behaviours from approximately 3-4 years of age but behavioural stereotypies are mostly absent. In this study, we investigated whether a mouse model of MPS-IIIA exhibited ASD-like symptoms. The BTBR T
Publisher: American Chemical Society (ACS)
Date: 02-07-2019
DOI: 10.1021/ACSCHEMNEURO.9B00328
Abstract: Heparan sulfate (HS) is a complex polysaccharide from the glycosaminoglycan (GAG) family that accumulates in tissues in several neurological lysosomal storage diseases known as mucopolysaccharidosis (MPS) disorders. The quantitation of HS in biological s les is important for studying MPS disorders but is very challenging because of its high molecular weight and heterogeneity. Recently, acid-catalyzed butanolysis followed by LC-MS/MS analysis has emerged as a promising method for the determination of HS. Butanolysis of HS produces fully desulfated disaccharide cleavage products which are detected by LC-MS/MS. Herein we describe the synthesis of butylated HS disaccharide standards and their use for determining the identity of major product peaks in LC-MS chromatograms from butanolysis of HS as well as the related GAGs heparin and heparosan. Furthermore, synthesis of a
Publisher: Mary Ann Liebert Inc
Date: 05-2016
DOI: 10.1089/HUM.2015.170
Abstract: Mucopolysaccharidosis type IIIA (MPS IIIA) is predominantly a disorder of the central nervous system, caused by a deficiency of sulfamidase (SGSH) with subsequent storage of heparan sulfate-derived oligosaccharides. No widely available therapy exists, and for this reason, a mouse model has been utilized to carry out a preclinical assessment of the benefit of intraparenchymal administration of a gene vector (AAVrh10-SGSH-IRES-SUMF1) into presymptomatic MPS IIIA mice. The outcome has been assessed with time, measuring primary and secondary storage material, neuroinflammation, and intracellular inclusions, all of which appear as the disease progresses. The vector resulted in predominantly ipsilateral distribution of SGSH, with substantially less detected in the contralateral hemisphere. Vector-derived SGSH enzyme improved heparan sulfate catabolism, reduced microglial activation, and, after a time delay, ameliorated GM3 ganglioside accumulation and halted ubiquitin-positive lesion formation in regions local to, or connected by projections to, the injection site. Improvements were not observed in regions of the brain distant from, or lacking connections with, the injection site. Intraparenchymal gene vector administration therefore has therapeutic potential provided that multiple brain regions are targeted with vector, in order to achieve widespread enzyme distribution and correction of disease pathology.
Publisher: Wiley
Date: 06-03-2014
DOI: 10.1002/RCM.6861
Abstract: Determination of genotype can be difficult, especially during the early stages of developing an animal model, e.g. when PCR primers are not yet available. An increase or decrease in specific metabolites can be used as a surrogate marker for genotype for instance, in homozygous MPS IIIA mice heparan sulphate (HS) is increased. A simple method was developed for extracting and depolymerising HS from mouse toe tissue using methanolysis under acidic conditions. The s le was lyophilised and resuspended in methanolic HCl. The reaction products are desulphated disaccharides and readily analysable by liquid chromatography/tandem mass spectrometry (LC/MS/MS) in positive ion multiple reaction monitoring mode. Measurements were normalised to a spiked deuterated HS internal standard and to endogenous chondroitin sulphate (CS). HS was measured in toe tissue taken from 30 mice in three groups of 10 (normal controls, MPS IIIA homozygotes and heterozygotes). A significant difference was observed between the MPS IIIA homozygotes and the other two groups, making it possible to identify mice with the MPS IIIA genotype based on the measurement of HS. Normalisation to CS was shown to correct for s le variability and reaction efficiency. Analysis of toe tissue provides a simple and rapid way of determining a storage phenotype at 5 to 7 days of age. Significantly, this method does not require any additional s les to be taken from animals, as it utilises tissue that is a by-product of toe clipping, a method that is routinely used to permanently identify mice.
Publisher: Elsevier BV
Date: 09-2019
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.BBR.2017.09.006
Abstract: The recent development of knock-in mouse models of Alzheimer's disease provides distinct advantages over traditional transgenic mouse models that rely on over-expression of amyloid precursor protein. Two such knock-in models that have recently been widely adopted by Alzheimer's researchers are the App
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.YMGME.2010.02.006
Abstract: Many viral backbones have been used as gene transfer vectors. However, the efficacy of therapy based on human-derived vectors may be limited by the high incidence of pre-existing humoral and cellular memory immunity. To circumvent some of the clinical disadvantages of vectors derived from common human pathogens, we have used an E1-deleted vector derived from a xenogenic adenovirus, canine adenovirus serotype 2 (CAV-2) to ameliorate neuropathological changes associated with the lysosomal storage disorder, mucopolysaccharidosis type IIIA (MPS IIIA). This presently untreatable condition is caused by N-sulfoglucosamine sulfohydrolase (SGSH) deficiency and is characterized by heparan sulfate accumulation and progressive neurodegeneration. Injection of CAV-SGSH-GFP into the thalamus of adult MPS IIIA mouse brain resulted in short-term gene expression. In contrast, intra-ventricular injection of newborn mice yielded dose-dependent transgene expression which persisted for at least 20-weeks and improved neuropathology. Together, these studies suggest that this E1-deleted CAV-2 vector is capable of mediating regional medium-term gene expression and facilitating improvements in neuropathology in MPS IIIA mice.
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.EXPNEUROL.2010.07.024
Abstract: Mucopolysaccharidosis type IIIA (MPS IIIA) is a neurodegenerative metabolic disorder caused by mutations in the N-sulfoglucosamine sulfohydrolase gene with resultant accumulation of partially degraded heparan sulfate (HS). Whilst allogeneic bone marrow transplantation (BMT) is indicated for several lysosomal storage disorders featuring neurodegeneration, its use in MPS III is highly controversial. Published evidence suggests that BMT does not improve cognitive function in MPS III patients. Despite this, patients continue to be transplanted in some centers. We therefore sought to determine the clinical effectiveness of BMT in a murine model of MPS IIIA. Pre-symptomatic young adult mice pre-conditioned with total body irradiation generated complete and stable donor-type chimerism. Whilst HS-derived disaccharides were reduced by up to 27% in the brain parenchyma, this was insufficient to decrease secondary cholesterol and GM3 ganglioside storage or permit clinical improvement. These results suggest that BMT is ineffective in its unmodified form and should not be considered as a treatment for MPS IIIA children.
Publisher: Wiley
Date: 27-04-2017
DOI: 10.1007/S10545-017-0044-4
Abstract: Mucopolysaccharidosis (MPS) type IIIA, or Sanfilippo syndrome, is a neurodegenerative lysosomal storage disorder caused by a deficiency of the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH), involved in the catabolism of heparan sulfate. The clinical spectrum is broad and the age of symptom onset and the degree of preservation of cognitive and motor functions appears greatly influenced by genotype. To explore this further, we generated a conditional knockout (Sgsh
Publisher: Cold Spring Harbor Laboratory
Date: 28-03-2023
DOI: 10.1101/2023.03.27.534462
Abstract: Sanfilippo syndrome, or mucopolysaccharidosis (MPS) types A, B, C or D, are neurodegenerative lysosomal storage disorders resulting from the lack of a specific enzyme involved in heparan sulfate (HS) catabolism. Several treatments are under evaluation for these conditions including substrate reduction therapy, with the most studied compound of this class being the isoflavone genistein. However, recent outcomes from a Phase III clinical trial have shown that high dose oral genistein does not significantly improve neurodevelopmental outcomes in MPS III patients. Here, we have tested an N -acetylglucosamine (GlcNAc) analogue inhibitor, 4-deoxy-GlcNAc peracetate, at reducing HS accumulation in cells from patients with Sanfilippo syndrome as a novel substrate reduction therapy. We then confirmed the capacity of this compound to modulate substrate accumulation in vivo in a Sanfilippo Drosophila model. Treatment with this compound significantly reduced HS in cultured MPS IIIA patient fibroblasts in a time-dependent manner. Neuronal and ubiquitous knockdown Drosophila models of MPS IIIC displaying elevated heparan sulfate and behavioural defects exhibited reduced HS burden relative to vehicle-treated controls following oral feeding with the GlcNAc analogue inhibitor. These findings indicate that this compound may be beneficial in slowing the accumulation of HS and may represent a novel therapeutic for Sanfilippo syndrome.
Publisher: Humana Press
Date: 2006
DOI: 10.1385/1-59745-037-5:471
Abstract: Lysosomal storage disorders are rare, inherited diseases caused by a deficiency of a specific, lysosomal enzyme. In the case of mucopolysaccharidosis type IIIA, a lack of active sulfamidase enzyme results in heparan sulfate accumulation, severe and progressive neurological deficits, and usually premature death. Embryonic stem cells can be genetically modified to overexpress lysosomal enzymes, providing a renewable reservoir of cells that can be readily expanded in culture. Screening clonal lines of embryonic stem cells for desirable properties such as high levels and maintenance of enzyme activity throughout terminal differentiation to neural phenotypes theoretically provides a reproducible population of cells that can be fully characterized in vitro before implantation within the central nervous system in animal models of lysosomal storage disorders.
Location: Australia
No related grants have been discovered for Adeline Lau.