Hurler and Hunter Syndromes: Mutual Correction of the Defect in Cultured Fibroblasts

Fratantoni, Joseph C.; Hall, Clara W.; Neufeld, Elizabeth F.

doi:10.1126/science.162.3853.570

Cited by 392 publications

(178 citation statements)

References 8 publications

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“…Correction of storage in neighboring cells occurs by endocytosis of secreted lysosomal enzymes from transduced cells. 20,21 Our studies in the MPSVII mouse have shown that the secreted GUSB can resolve lysosomal storage lesion in the brain at least 2 mm away from GUSB positively stained cells. 3,21 This shows that although enzyme was present in neighboring untransduced cells, it was below the level of histochemical detection.…”

Section: Aav In the Cat Brain Ch Vite Et Almentioning

confidence: 91%

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Adeno-associated virus vector-mediated transduction in the cat brain

et al. 2003

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Adeno-associated virus (AAV) vectors are capable of delivering a therapeutic gene to the mouse brain that can result in long-term and widespread protein production. However, the human infant brain is more than 1000 times larger than the mouse brain, which will make the treatment of global neurometabolic disorders in children more difficult. In this study, we evaluated the ability of three AAV serotypes (1,2, and 5) to transduce cells in the cat brain as a model of a large mammalian brain. The human lysosomal enzyme bglucuronidase (GUSB) was used as a reporter gene, because it can be distinguished from feline GUSB by heat stability. The vectors were injected into the cerebral cortex, caudate nucleus, thalamus, corona radiata, internal capsule, and centrum semiovale of 8-week-old cats. The brains were evaluated for gene expression using in situ hybridization and enzyme histochemistry 10 weeks after surgery. The AAV2 vector was capable of transducing cells in the gray matter, while the AAV1 vector resulted in greater transduction of the gray matter than AAV2 as well as transduction of the white matter. AAV5 did not result in detectable transduction in the cat brain.

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Section: Aav In the Cat Brain Ch Vite Et Almentioning

confidence: 91%

“…Since GUSB is a secreted enzyme that is endocytosed by neighboring untransduced cells, 20,21 we determined whether histochemically positive cells were cross-corrected or whether they expressed GUSB mRNA. In all …”

Section: In Situ Hybridizationmentioning

confidence: 99%

Adeno-associated virus vector-mediated transduction in the cat brain

et al. 2003

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“…8 Moreover, NaGlu shares many properties with other lysosomal enzymes, which can be secreted and taken up by neighboring cells and transported to the lysosomes, resulting in broader distribution via a bystander effect. [9][10][11] Generally speaking, for MPS disorders, only 1-2% residual enzyme activity may be needed to normalize cell function. Therefore, it would not be necessary to transduce all cells for effective MPS IIIB treatment.…”

Section: Introductionmentioning

confidence: 99%

Significantly increased lifespan and improved behavioral performances by rAAV gene delivery in adult mucopolysaccharidosis IIIB mice

Jennings

et al. 2007

Gene Ther

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Mucopolysaccharidosis (MPS) IIIB is an inherited lysosomal storage disease, caused by the deficiency of a-N-acetylglucosaminidase (NaGlu), resulting in severe global neurological involvement with high mortality. One major hurdle in therapeutic development for MPS IIIB is the presence of the blood-brain barrier, which impedes the global central nervous system (CNS) delivery of therapeutic materials. In this study, we used a minimal invasive strategy, combining an intravenous (i.v.) and an intracisternal (i.c.) injection, following an i.v. infusion of mannitol, to complement the CNS delivery of adeno-associated viral (AAV) vector for treating MPS IIIB in young adult mice. This treatment resulted in a significantly prolonged lifespan of MPS IIIB mice (11.1-19.5 months), compared with that without treatment (7.9-11.3), and correlated with significantly improved behavioral performances, the restoration of functional NaGlu, and variable correction of lysosomal storage pathology in the CNS, as well as in different somatic tissues. This study demonstrated the great potential of combining i.v. and i.c. administration for improving rAAV CNS gene delivery and developing rAAV gene therapy for treating MPS IIIB in patients.

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“…In animal models, cells derived from human hematopoietic stem and progenitor cells can have widespread, nonhematopoietic tissue distribution (21). The engrafting cells remain hematopoietic (22,23) and can be present in many tissues, including nervous tissue, in the form of microglial cells and tissue macrophages and can provide the enzyme to neighboring affected cells (18), a concept recognized in tissue culture experiments in the 1960s (24).…”

Section: Inherited Metabolic Disordersmentioning

confidence: 99%