Bicistronic lentiviral vector corrects β-hexosaminidase deficiency in transduced and cross-corrected human Sandhoff fibroblasts

Arfi, Audrey; Bourgoin, Christophe; Basso, Luisa; Emiliani, Carla; Tancini, Brunella; Chigorno, Vanna; Li, Yu-Teh; Orlacchio, Aldo; Poënaru, Livia; Sonnino, Sandro; Caillaud, Catherine

doi:10.1016/j.nbd.2005.04.017

Cited by 32 publications

(26 citation statements)

References 41 publications

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“…The internalized activity, even if low, was sufficient to restore proper GM2 catabolism. These [318] and similar [319] results suggest that this strategy is a useful alternative to direct gene therapy to cure these diseases.…”

Section: Targeting Sphingolipid Metabolism and Cellular Organization:mentioning

confidence: 54%

Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders

et al. 2010

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Sphingolipids are polar membrane lipids present as minor components in eukaryotic cell membranes. Sphingolipids are highly enriched in nervous cells, where they exert important biological functions. They deeply affect the structural and geometrical properties and the lateral order of cellular membranes, modulate the function of several membrane-associated proteins, and give rise to important intra- and extracellular lipid mediators. Sphingolipid metabolism is regulated along the differentiation and development of the nervous system, and the expression of a peculiar spatially and temporarily regulated sphingolipid pattern is essential for the maintenance of the functional integrity of the nervous system: sphingolipids in the nervous system participate to several signaling pathways controlling neuronal survival, migration, and differentiation, responsiveness to trophic factors, synaptic stability and synaptic transmission, and neuron-glia interactions, including the formation and stability of central and peripheral myelin. In several neurodegenerative diseases, sphingolipid metabolism is deeply deregulated, leading to the expression of abnormal sphingolipid patterns and altered membrane organization that participate to several events related to the pathogenesis of these diseases. The most impressive consequence of this deregulation is represented by anomalous sphingolipid-protein interactions that are at least, in part, responsible for the misfolding events that cause the fibrillogenic and amyloidogenic processing of disease-specific protein isoforms, such as amyloid beta peptide in Alzheimer's disease, huntingtin in Huntington's disease, alpha-synuclein in Parkinson's disease, and prions in transmissible encephalopathies. Targeting sphingolipid metabolism represents today an underexploited but realistic opportunity to design novel therapeutic strategies for the intervention in these diseases.

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Section: Targeting Sphingolipid Metabolism and Cellular Organization:mentioning

confidence: 54%

Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders

et al. 2010

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“…An important principle of gene therapy for lysosomal diseases is the phenomenon of cross-correction, where a genetically corrected cell can release enzymes for uptake by neighboring cells. As a proof of principle for the validity of this approach, in the case of Sandhoff disease infection with a bicistronic lentiviral vector, containing both human HEXA and HEXB cDNAs, was able to restore hexosaminidase expression and activity in Sandhoff fibroblasts [86]. The enzyme secreted in the culture medium by infected fibroblasts was internalized by the deficient cells via mannose 6-phosphate receptor-mediated endocytosis, and the internalized activity was sufficient to restore proper GM2 catabolism in Sandhoff fibroblasts [86,87].…”

Section: Unexpected Alterations Of Sphingolipid Metabolism In Sphingomentioning

confidence: 99%

“…As a proof of principle for the validity of this approach, in the case of Sandhoff disease infection with a bicistronic lentiviral vector, containing both human HEXA and HEXB cDNAs, was able to restore hexosaminidase expression and activity in Sandhoff fibroblasts [86]. The enzyme secreted in the culture medium by infected fibroblasts was internalized by the deficient cells via mannose 6-phosphate receptor-mediated endocytosis, and the internalized activity was sufficient to restore proper GM2 catabolism in Sandhoff fibroblasts [86,87]. The reactivation of the defective enzyme (e.g., b-glucosidase in an animal model of Gaucher disease (GD)) has been also obtained by the use of ''chemical chaperones'', small molecules directly interacting with the enzyme [88].…”

Section: Unexpected Alterations Of Sphingolipid Metabolism In Sphingomentioning

confidence: 99%

Secondary Alterations of Sphingolipid Metabolism in Lysosomal Storage Diseases

et al. 2011

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In several neurodegenerative diseases, sphingolipid metabolism is deeply deregulated, leading to the expression of abnormal membrane sphingolipid patterns and altered plasma membrane organization. In this paper, we review the potential importance of these alterations to the pathogenesis of these diseases and focus the reader's attention on some secondary alterations of sphingolipid metabolism that have been sporadically reported in the literature. Moreover, we present a detailed analysis of the lipid composition of different central nervous system and extraneural tissues from the acid sphingomyelinase-deficient mouse, the animal model for Niemann-Pick disease type A, characterized by the accumulation of sphingomyelin. Our data show an unexpected, tissue specific selection of the accumulated molecular species of sphingomyelin, and an accumulation of GM3 and GM2 gangliosides in both neural and extraneural tissues, that cannot be solely explained by the lack of acid sphingomyelinase.

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“…Because optimal production of HexA is suggested to require coexpression of both Hex subunits, [3][4][5] SD mice were treated by bilateral injections of the striatum and deep cerebellar nuclei (DCN) with monocistronic vectors expressing human Hex α-and β-subunits, both with carboxyl terminal fusions to the HIV Tat protein transduction domain. 6 Treated mice routinely survived to 2 years, the maximum age permitted by institutional animal welfare mandates.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Response in Feline Sandhoff Disease Despite Immunity to Intracranial Gene Therapy

et al. 2013

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Salutary responses to adeno-associated viral (AAV) gene therapy have been reported in the mouse model of Sandhoff disease (SD), a neurodegenerative lysosomal storage disease caused by deficiency of β-N-acetylhexosaminidase (Hex). While untreated mice reach the humane endpoint by 4.1 months of age, mice treated by a single intracranial injection of vectors expressing human hexosaminidase may live a normal life span of 2 years. When treated with the same therapeutic vectors used in mice, two cats with SD lived to 7.0 and 8.2 months of age, compared with an untreated life span of 4.5 ± 0.5 months (n = 11). Because a pronounced humoral immune response to both the AAV1 vectors and human hexosaminidase was documented, feline cDNAs for the hexosaminidase α- and β-subunits were cloned into AAVrh8 vectors. Cats treated with vectors expressing feline hexosaminidase produced enzymatic activity >75-fold normal at the brain injection site with little evidence of an immune infiltrate. Affected cats treated with feline-specific vectors by bilateral injection of the thalamus lived to 10.4 ± 3.7 months of age (n = 3), or 2.3 times as long as untreated cats. These studies support the therapeutic potential of AAV vectors for SD and underscore the importance of species-specific cDNAs for translational research.

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Bicistronic lentiviral vector corrects β-hexosaminidase deficiency in transduced and cross-corrected human Sandhoff fibroblasts

Cited by 32 publications

References 41 publications

Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders

Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders

Secondary Alterations of Sphingolipid Metabolism in Lysosomal Storage Diseases

Therapeutic Response in Feline Sandhoff Disease Despite Immunity to Intracranial Gene Therapy

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