Increased longevity and metabolic correction following syngeneic BMT in a murine model of mucopolysaccharidosis type I

Wolf, Daniel; Lenander, A W; Nan, Zhenhong; Braunlin, Elizabeth; Podetz-Pedersen, Kelly M.; Whitley, Chester B.; Gupta, Pankaj; Low, Walter C.; McIvor, R. Scott

doi:10.1038/bmt.2011.239

Cited by 6 publications

(2 citation statements)

References 33 publications

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“…Possibly other brain abnormalities such as mental retardation may underlie the ataxia phenotype and/or the patients die before developing it. As improvements verified after enzyme replacement therapy and hematopoietic stem cell transplantation are leading patients to better quality of life [18] and a possible increase in life spam [19], it is possible that impairment in cerebellar function may develop in these patients and could be clinically relevant.…”

Section: Discussionmentioning

confidence: 99%

Evidence of a progressive motor dysfunction in Mucopolysaccharidosis type I mice

Baldo

Mayer

Martinelli

et al. 2012

Behavioural Brain Research

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Mucopolysaccharidosis (MPS) type I (Hurler syndrome) is a lysosomal storage disorder characterized by deficiency of alpha-L-iduronidase (IDUA), intracellular storage of glycosaminoglycans (GAGs) and progressive neurological pathology. The MPS I mouse model provides an opportunity to study the pathophysiology of this disorder and to determine the efficacy of novel therapies. Previous work has demonstrated a series of abnormalities in MPS I mice behavior, but so far some important brain functions have not been addressed. Therefore, in the present study we aimed to determine if MPS I mice have motor abnormalities, and at what age they become detectable. MPS I and normal male mice from 2 to 8 months of age were tested in open-field for locomotor activity, hindlimb gait analysis and hang wire performance. We were able to detect a progressive reduction in the crossings and rearings in the open field test and in the hang wire test in MPS I mice from 4 months, as well as a reduction in the gait length at 8 months. Histological examination of 8-month old mice cortex and cerebellum revealed storage of GAGs in Purkinje cells and neuroinflammation, evidenced by GFAP immunostaining. However TUNEL staining was negative, suggesting that death does not occur. Our findings suggest that MPS I mice have a progressive motor dysfunction, which is not caused by loss of neuron cells but might be related to a neuroinflammatory process.

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Section: Discussionmentioning

confidence: 99%

Evidence of a progressive motor dysfunction in Mucopolysaccharidosis type I mice

Baldo

Mayer

Martinelli

et al. 2012

Behavioural Brain Research

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“…It shares many systemic manifestations that are found in the attenuated forms, such as growth retardation hepatosplenomegaly, joint stiffness, heart disease and respiratory insufficiency. However, it is rapidly progressive, presents progressive neurodegeneration and death usually occurs during the first decade of life [ 1 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Enzyme Replacement Therapy Started Late in a Murine Model of Mucopolysaccharidosis Type I

et al. 2015

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Mucopolysaccharidosis type I (MPS I) is a progressive disorder caused by deficiency of α-L-iduronidase (IDUA), which leads to storage of heparan and dermatan sulphate. It is suggested that early enzyme replacement therapy (ERT) leads to better outcomes, although many patients are diagnosed late and don’t receive immediate treatment. This study aims to evaluate the effects of late onset ERT in a MPS I murine model. MPS I mice received treatment from 6 to 8 months of age (ERT 6–8mo) with 1.2mg laronidase/kg every 2 weeks and were compared to 8 months-old wild-type (Normal) and untreated animals (MPS I). ERT was effective in reducing urinary and visceral GAG to normal levels. Heart GAG levels and left ventricular (LV) shortening fraction were normalized but cardiac function was not completely improved. While no significant improvements were found on aortic wall width, treatment was able to significantly reduce heart valves thickening. High variability was found in behavior tests, with treated animals presenting intermediate results between normal and affected mice, without correlation with cerebral cortex GAG levels. Cathepsin D activity in cerebral cortex also did not correlate with behavior heterogeneity. All treated animals developed anti-laronidase antibodies but no correlation was found with any parameters analyzed. However, intermediary results from locomotion parameters analyzed are in accordance with intermediary levels of heart function, cathepsin D, activated glia and reduction of TNF-α expression in the cerebral cortex. In conclusion, even if started late, ERT can have beneficial effects on many aspects of the disease and should be considered whenever possible.

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Gene therapy for neurodegenerative diseases

O’Connor

Boulis

2015

Trends in Molecular Medicine

113

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Increased longevity and metabolic correction following syngeneic BMT in a murine model of mucopolysaccharidosis type I

Cited by 6 publications

References 33 publications

Evidence of a progressive motor dysfunction in Mucopolysaccharidosis type I mice

Evidence of a progressive motor dysfunction in Mucopolysaccharidosis type I mice

Effects of Enzyme Replacement Therapy Started Late in a Murine Model of Mucopolysaccharidosis Type I

Gene therapy for neurodegenerative diseases

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