Abstract: A lysosomal storage disease, identified as a mucopolysaccharidosis (MPS), was diagnosed... more Abstract: A lysosomal storage disease, identified as a mucopolysaccharidosis (MPS), was diagnosed in a free-living Kaka (Nestor meridionalis), an endemic New Zealand parrot, which exhibited weakness, incoordination, and seizures. Histopathology showed typical colloid-like cytoplasmic inclusions in Purkinje cells and many other neurons throughout the brain. Electron microscopy revealed that storage bodies contained a variety of linear, curved, or circular membranous profiles and electron-dense bodies. Because the bird came from a small isolated population of Kaka in the northern South Island, a genetic cause was deemed likely. Tandem mass spectrometry revealed increased levels of heparan sulfate-derived disaccharides in the brain and liver compared with tissues from controls. Enzymatic assays documented low levels of iduronate-2-sulfatase activity, which causes a lysosomal storage disorder called MPS type II or Hunter syndrome. A captive breeding program is currently in progress, and the possibility of detecting carriers of this disorder warrants further investigation.
The mucopolysaccharidoses (MPS) are a subgroup of lysosomal storage disorders that are caused by ... more 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).
The recent development of knock-in mouse models of Alzheimer's disease provides distinct ... more 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(NL-F) and App(NL-G-F) mice. This study aimed to further characterise the behavioural phenotype and amyloid plaque distribution of App(NL-G-F/NL-G-F) (C57BL/6J background) mice at six-months of age. An attempt to replicate a previous study that observed deficits in working memory in the Y-maze, showed no difference between App(NL-G-F/NL-G-F) and wild-type mice. Further assessment of these mice using the novel object recognition test and Morris water maze also revealed no differences between App(NL-G-F/NL-G-F) and wild-type mice. Despite a lack of demonstrated cognitive deficits, we report a reduction in locomotor/exploratory activity in an open field. Histological examination of App(NL-G-F/NL-G-F) mice showed widespread distribution of amyloid plaques at this age. We conclude that whilst at six-months of age, memory deficits are not sufficiently robust to be replicated in varying environments, amyloid plaque burden is significant in App(NL-G-F/NL-G-F) knock-in brain.
Journal of inherited metabolic disease, Jan 27, 2017
Mucopolysaccharidosis (MPS) type IIIA, or Sanfilippo syndrome, is a neurodegenerative lysosomal s... more 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 (KO) ) mouse model with ubiquitous Sgsh deletion, and compared the clinical and pathological phenotype with that of the spontaneous Sgsh (D31N) MPS-IIIA mouse model. Phenotypic deficits were noted in Sgsh (KO) mice prior to Sgsh (D31N) mice, however these outcomes did not correlate with any shift in the time of appearance nor rate of accumulation of primary (heparan sulfate) or secondary substrates (GM2/GM3 gangliosides). Other disease lesions (elevations in lysosomal integral membrane protein-II expression, rea...
Mucopolysaccharidosis type IIIA (MPS IIIA) is predominantly a disorder of the central nervous sys... more 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 utilised to carry out a pre-clinical assessment of the benefit of intraparenchymal administration of a gene vector (AAVrh10-SGSH-IRES-SUMF1) into pre-symptomatic 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 format...
Lysosomal storage disorders are rare, inherited diseases caused by a deficiency of a specific, ly... more 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.
Abstract: A lysosomal storage disease, identified as a mucopolysaccharidosis (MPS), was diagnosed... more Abstract: A lysosomal storage disease, identified as a mucopolysaccharidosis (MPS), was diagnosed in a free-living Kaka (Nestor meridionalis), an endemic New Zealand parrot, which exhibited weakness, incoordination, and seizures. Histopathology showed typical colloid-like cytoplasmic inclusions in Purkinje cells and many other neurons throughout the brain. Electron microscopy revealed that storage bodies contained a variety of linear, curved, or circular membranous profiles and electron-dense bodies. Because the bird came from a small isolated population of Kaka in the northern South Island, a genetic cause was deemed likely. Tandem mass spectrometry revealed increased levels of heparan sulfate-derived disaccharides in the brain and liver compared with tissues from controls. Enzymatic assays documented low levels of iduronate-2-sulfatase activity, which causes a lysosomal storage disorder called MPS type II or Hunter syndrome. A captive breeding program is currently in progress, and the possibility of detecting carriers of this disorder warrants further investigation.
The mucopolysaccharidoses (MPS) are a subgroup of lysosomal storage disorders that are caused by ... more 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).
The recent development of knock-in mouse models of Alzheimer's disease provides distinct ... more 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(NL-F) and App(NL-G-F) mice. This study aimed to further characterise the behavioural phenotype and amyloid plaque distribution of App(NL-G-F/NL-G-F) (C57BL/6J background) mice at six-months of age. An attempt to replicate a previous study that observed deficits in working memory in the Y-maze, showed no difference between App(NL-G-F/NL-G-F) and wild-type mice. Further assessment of these mice using the novel object recognition test and Morris water maze also revealed no differences between App(NL-G-F/NL-G-F) and wild-type mice. Despite a lack of demonstrated cognitive deficits, we report a reduction in locomotor/exploratory activity in an open field. Histological examination of App(NL-G-F/NL-G-F) mice showed widespread distribution of amyloid plaques at this age. We conclude that whilst at six-months of age, memory deficits are not sufficiently robust to be replicated in varying environments, amyloid plaque burden is significant in App(NL-G-F/NL-G-F) knock-in brain.
Journal of inherited metabolic disease, Jan 27, 2017
Mucopolysaccharidosis (MPS) type IIIA, or Sanfilippo syndrome, is a neurodegenerative lysosomal s... more 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 (KO) ) mouse model with ubiquitous Sgsh deletion, and compared the clinical and pathological phenotype with that of the spontaneous Sgsh (D31N) MPS-IIIA mouse model. Phenotypic deficits were noted in Sgsh (KO) mice prior to Sgsh (D31N) mice, however these outcomes did not correlate with any shift in the time of appearance nor rate of accumulation of primary (heparan sulfate) or secondary substrates (GM2/GM3 gangliosides). Other disease lesions (elevations in lysosomal integral membrane protein-II expression, rea...
Mucopolysaccharidosis type IIIA (MPS IIIA) is predominantly a disorder of the central nervous sys... more 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 utilised to carry out a pre-clinical assessment of the benefit of intraparenchymal administration of a gene vector (AAVrh10-SGSH-IRES-SUMF1) into pre-symptomatic 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 format...
Lysosomal storage disorders are rare, inherited diseases caused by a deficiency of a specific, ly... more 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.
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