Adeno-Associated Virus as a Vector for Liver-Directed Gene Therapy

Xiao, Weidong; Berta, Scott C.; Lü, Min; Moscioni, Albert D.; Tazelaar, John; Wilson, James M.

doi:10.1128/jvi.72.12.10222-10226.1998

Cited by 151 publications

(40 citation statements)

References 26 publications

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“…Intense GUSB staining was observed in some cells in the liver that morphologically resembled hepatocytes ( Fig. 2A), the main target of AAV2 in the liver (Xiao et al 1998). In contrast, no punctate staining was seen in extrahepatic tissues, such as the spleen (Fig.…”

Section: Gusb Expression and Distributionmentioning

confidence: 96%

Clinical response to persistent, low‐level β‐glucuronidase expression in the murine model of mucopolysaccharidosis type VII

Donsante¹,

Levy

Vogler

et al. 2007

J of Inher Metab Disea

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Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by beta-glucuronidase (GUSB) deficiency. This disease exhibits a broad spectrum of clinical signs including skeletal dysplasia, retinal degeneration, cognitive deficits and hearing impairment. Sustained, high-level expression of GUSB significantly improves the clinical course of the disease in the murine model of MPS VII. Low levels of enzyme expression (1-5% of normal) can significantly reduce the biochemical and histopathological manifestations of MPS VII. However, it has not been clear from previous studies whether persistent, low levels of circulating GUSB lead to significant improvements in the clinical presentation of this disease. We generated a rAAV2 vector that mediates persistent, low-level GUSB expression in the liver. Liver and serum levels of GUSB were maintained at approximately 5% and approximately 2.5% of normal, respectively, while other tissue ranged from background levels to 0.9%. This level of activity significantly reduced the secondary elevations of alpha-galactosidase and the levels of glycosaminoglycans in multiple tissues. Interestingly, this level of GUSB was also sufficient to reduce lysosomal storage in neurons in the brain. Although there were small but statistically significant improvements in retinal function, auditory function, skeletal dysplasia, and reproduction in rAAV-treated MPS VII mice, the clinical deficits were still profound and there was no improvement in lifespan. These data suggest that circulating levels of GUSB greater than 2.5% will be required to achieve substantial clinical improvements in MPS VII.

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Section: Gusb Expression and Distributionmentioning

confidence: 96%

Clinical response to persistent, low‐level β‐glucuronidase expression in the murine model of mucopolysaccharidosis type VII

Donsante¹,

Levy

Vogler

et al. 2007

J of Inher Metab Disea

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show abstract

“…The advantage of using liver-specific promoters is that they primarily transduce hepatocytes, thereby avoiding expression in antigen-presenting (Kupffer) cells. Additionally, liver-specific promoters might induce a desirable increase in expression compared to the CMV promoter, as has previously been suggested [14,26]. In this light, we tested rAAV8 vectors containing various transgenic cassettes with five liver-specific promoter/enhancer combinations ( Figure 1).…”

Section: Liver-specific Promoter/enhancer Combinations Increase Hapoamentioning

confidence: 97%

AAV gene therapy as a means to increase apolipoprotein (Apo) A‐I and high‐density lipoprotein‐cholesterol levels: correction of murine ApoA‐I deficiency

Vaessen

Veldman

Comijn

et al. 2009

The Journal of Gene Medicine

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The present study demonstrates that systemic delivery of a scAAV8 vector provides a means for efficient liver expression of hApoA-I, thereby correcting the lipid abnormalities associated with murine ApoA-I deficiency. Importantly, the study demonstrates that AAV-based gene therapy can be used to express therapeutic proteins at a high level for a prolonged period of time and, as such, provides a basis for further development of this strategy to treat hApoA-I deficiency.

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“…Based on the specificity of the liver to AAVs, we consider that rAAV may be an ideal vector in liver transplantation. 13 The study by Halbert et al 14 showed that efficient rAAV transduction had an area-limiting potency in bronchial epithelium in which a balloon catheter was lodged, indicating possible roles of trauma in rAAVmediated delivery. [15][16][17] In organ transplantation, unavoidable ischemia-reperfusion injury results in damage to cells and subsequent repair of injured structures.…”

mentioning

confidence: 99%

Recombinant adeno-associated virus vector: Is it ideal for gene delivery in liver transplantation?

Yang

Wu²,

Tsui

et al. 2003

Liver Transplantation

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Adeno-Associated Virus as a Vector for Liver-Directed Gene Therapy

Cited by 151 publications

References 26 publications

Clinical response to persistent, low‐level β‐glucuronidase expression in the murine model of mucopolysaccharidosis type VII

Clinical response to persistent, low‐level β‐glucuronidase expression in the murine model of mucopolysaccharidosis type VII

AAV gene therapy as a means to increase apolipoprotein (Apo) A‐I and high‐density lipoprotein‐cholesterol levels: correction of murine ApoA‐I deficiency

Recombinant adeno-associated virus vector: Is it ideal for gene delivery in liver transplantation?

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