Induced secretion of β-hexosaminidase by human brain endothelial cells: A novel approach in Sandhoff disease?

Batista, Lévy; Miller, Florence; Clave, Céline; Arfi, Audrey; Douillard-Guilloux, Gaëlle; Couraud, Pierre‐Olivier; Caillaud, Catherine

doi:10.1016/j.nbd.2009.12.001

Cited by 7 publications

(7 citation statements)

References 27 publications

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“…Even in the absence of established treatments for the GM2 gangliosidoses, early identification is critical; not only may it inform reproductive choice for parents and relatives of the proband, but it clarifies management and obviates the need for further, often invasive, investigations. In the long term, the promise of definitive therapies based on specific molecular understanding of the disease provides a strong impetus for detailed study and timely diagnosis; clinical trials of pharmacological chaperones in juvenile‐ and adult‐onset disease 35–37 provide early encouragement, and gene transfer techniques to introduce functional copies of the β‐hexosaminidase gene are in development in the light of positive preclinical findings 38–40 . While UK population screening for the GM2 gangliosidoses (utilizing enzymatic assay and molecular analysis of common mutations) is currently limited to TSD within the Jewish community, 21 the relatively high rates of disease in Pakistani families evident in this study suggest a potential benefit from similar approaches within this ethnic group.…”

Section: Discussionmentioning

confidence: 99%

GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed

Smith¹,

Winstone²,

Stellitano³

et al. 2011

Develop Med Child Neuro

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Aim To report the demographic, phenotypic, and time‐to‐diagnosis characteristics of children with GM2 gangliosidosis referred to the UK study of Progressive Intellectual and Neurological Deterioration. Method Case notification is made via monthly surveillance card, administered by the British Paediatric Surveillance Unit to all UK‐based paediatricians; children with GM2 gangliosidosis were identified from cases satisfying inclusion in the UK study of Progressive Intellectual and Neurological Deterioration and analysed according to phenotypic and biochemical categories. Results Between May 1997 and January 2010, 73 individuals with GM2 gangliosidoses were reported: 40 with Tay–Sachs disease, 31 with Sandhoff disease, and two with GM2 activator protein deficiency. Together they account for 6% (73/1164) of all diagnosed cases of progressive intellectual and neurological deterioration. The majority (62/73) were sporadic index cases with no family history. Children of Pakistani ancestry were overrepresented in all subtypes, particularly juvenile Sandhoff disease, accounting for 10 of 11 notified cases. Infantile‐onset variants predominated (55/73); the mean age at onset of symptoms was 6.2 and 4.7 months for infantile‐onset Tay–Sachs and Sandhoff disease respectively, and 26.2 and 34.7 months for the corresponding juvenile‐onset variants. Time to diagnosis averaged 7.4 months and 28.0 months in infantile‐ and juvenile‐onset disease respectively. Interpretation GM2 gangliosidosis is a significant cause of childhood neurodegenerative disease; timely diagnosis relies upon improved clinical recognition, which may be increasingly important as specific therapies become available. There is a potential benefit from the introduction of screening programmes for high‐risk ethnic groups.

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Section: Discussionmentioning

confidence: 99%

GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed

Smith¹,

Winstone²,

Stellitano³

et al. 2011

Develop Med Child Neuro

View full text Add to dashboard Cite

show abstract

“…Therapeutic approaches such as bone-marrow transplantation [ 320 ], enzyme-replacement therapy with recombinant highly phosphomannosylated β -hexosaminidase A [ 321 ], or transplantation of neural stem cells [ 322 ] have been investigated in the animal model of the 0 variant, substrate-reduction therapy with N -butyl deoxynojirimycin [ 323 , 324 ], and with pyrimethamine as pharmacological chaperone [ 325 , 326 ] in adult patients and gene therapy in endothelial cells [ 327 ]. Treatment of the accompanying inflammation is beneficial [ 328 ].…”

Section: Pathobiochemistrymentioning

confidence: 99%

Ganglioside Biochemistry

2012

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“…As target we chose endothelial cells in the CNS, which are readily accessible from systemic circulation, form a stable nonproliferating cell population, and are able to release lysosomal enzymes. 19,20 Importantly, previous work has shown that transducing brain microcapillary endothelial cells provides a strategy for gene delivery and for treating lysosomal disorders. 21 We have developed a unique AAV vector (AAV-BR1) which, when systemically administered, is capable of transducing CNS endothelial cells and leading to a sustained gene expression.…”

Section: Introductionmentioning

confidence: 99%

Brain endothelial specific gene therapy improves experimental Sandhoff disease

Dogbevia

Othman

Penno

et al. 2019

J Cereb Blood Flow Metab

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In Tay-Sachs and Sandhoff disease, a deficiency of the lysosomal enzyme β-hexosaminidase causes GM2 and other gangliosides to accumulate in neurons and triggers neurodegeneration. Although the pathology centers on neurons, β-hexosaminidase is mainly expressed outside of neurons, suggesting that gene therapy of these diseases should target non-neuronal cells to reconstitute physiological conditions. Here, we tested in Hexb−/− mice, a model of Sandhoff disease, to determine whether endothelial expression of the genes for human β-hexosaminidase subunit A and B ( HEXA, HEXB) is able to reduce disease symptoms and prolong survival of the affected mice. The brain endothelial selective vectors AAV-BR1-CAG- HEXA and AAV-BR1-CAG- HEXB transduced brain endothelial cells, which subsequently released β-hexosaminidase enzyme. In vivo intravenous administration of the gene vectors to adult and neonatal mice prolonged survival. They improved neurological function and reduced accumulation of the ganglioside GM2 and the glycolipid GA2 as well as astrocytic activation. Overall, the data demonstrate that endothelial cells are a suitable target for intravenous gene therapy of GM2 gangliosidoses and possibly other lysosomal storage disorders.

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Induced secretion of β-hexosaminidase by human brain endothelial cells: A novel approach in Sandhoff disease?

Cited by 7 publications

References 27 publications

GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed

GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed

Ganglioside Biochemistry

Brain endothelial specific gene therapy improves experimental Sandhoff disease

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