AAV8‐mediated expression of glucocerebrosidase ameliorates the storage pathology in the visceral organs of a mouse model of Gaucher disease

McEachern, Kerry Anne; Nietupski, Jennifer B.; Chuang, Wei-Lien; Armentano, Donna; Johnson, Jodie V.; Hutto, Elizabeth; Grabowski, Gregory A.; Cheng, Seng H.; Marshall, John

doi:10.1002/jgm.901

Cited by 58 publications

(40 citation statements)

References 51 publications

(64 reference statements)

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“…For the enzyme alone and combination therapy studies, Fabry mice were first immunotolerized to the recombinant human enzyme by treating the animals with a recombinant AAV vector encoding an inactive, but stable mutant form of α-Gal A (point mutation in amino acid 170). We and others have previously shown that AAVmediated hepatic-restricted expression of proteins resulted in the induction of immune tolerance to the expressed protein (22,(28)(29)(30)(31)(32). Administration of rh α-Gal A into AAV2/8 α-galD170Mut-treated Fabry mice did not elicit antibodies to the enzyme (data not shown).…”

Section: Combination Therapy With Genz-682452 and α-Galactosidase A Imentioning

confidence: 77%

Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease

Ashe¹,

Budman²,

Bangari³

et al. 2015

Mol Med

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Section: Combination Therapy With Genz-682452 and α-Galactosidase A Imentioning

confidence: 77%

Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease

Ashe¹,

Budman²,

Bangari³

et al. 2015

Mol Med

Self Cite

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“…Recent studies show some rAAV vectors including serotypes 1, 2, and 5 can transduce dendritic cells (DCs) and generate immune responses to transgene products (6)(7)(8)(9). Some studies have shown that rAAV8 vector has a low immunogenicity while it transduces liver, muscle, and many other cell types with high efficiency (10)(11)(12)(13)(14)(15). The work done by Vandenberghe and colleagues suggests that this is due to the inability of transduction of DCs (8).…”

mentioning

confidence: 99%

Distinct immune responses to transgene products from rAAV1 and rAAV8 vectors

Song

2009

Proc. Natl. Acad. Sci. U.S.A.

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Recently developed serotypes of recombinant adeno-associated virus (rAAV) vectors have significantly enhanced the use of rAAV vectors for gene therapy. However, host immune responses to the transgene products from different serotypes remain uncharacterized. In the present study, we evaluated the differential immune responses to the transgene products from rAAV1 and rAAV8 vectors. In non-obese diabetic (NOD) mice, which have a hypersensitive immunity, rAAV serotype 1 vector (rAAV1-hAAT) induced high levels of both humoral and cellular responses, while rAAV8-hAAT did not. In vitro studies showed that rAAV1, but not rAAV8 vector transduced dendritic cells (DCs) efficiently. In vivo studies indicated that vector transduction of DCs was essential for the immune responses; while the presence of a transgene product (or foreign gene product produced by host cells) was not immunogenic. Intriguingly, preimmunization with rAAV8-hAAT vector or with serum of hAAT transgenic NOD mouse induced immune tolerance to rAAV1-hAAT injection. These results demonstrate the immunogenic differences of rAAV1 and rAAV8 and imply tremendous potential for these vectors in different applications, where an immune response to transgene is to be either elicited or avoided. DC activation ͉ rAAV vectors

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“…AAV2=a-Gal contained serotype 2 inverted terminal repeats and the human a-Gal cDNA under the control of the DC190 liver-restricted promoter (Ziegler et al, 2004;Barbon et al, 2005;McEachern et al, 2006). Recombinant vectors were produced by triple-plasmid transfection of 293 cells and were column purified as reported (O'Riordan et al, 2000).…”

Section: Generation Of Viral Vectorsmentioning

confidence: 99%

Cytotoxic T Lymphocyte Responses to Transgene Product, Not Adeno-Associated Viral Capsid Protein, Limit Transgene Expression in Mice

Siders¹,

Shields²,

Kaplan³

et al. 2009

Human Gene Therapy

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The use of adeno-associated viral (AAV) vectors for gene replacement therapy is currently being explored in several clinical indications. However, reports have suggested that input capsid proteins from AAV-2 vector particles may result in the stimulation of cytotoxic T lymphocyte (CTL) responses that can result in a loss of transduced cells. To explore the impact of anti-AAV CTLs on AAV-mediated transgene expression, both immunocompetent C57BL=6 mice and B cell-deficient mMT mice were immunized against the AAV2 capsid protein (Cap) and were injected intravenously with an AAV-2 vector encoding a-galactosidase (a-Gal). C57BL=6 mice, which developed both CTL and neutralizing antibody responses against Cap, failed to show any detectable a-Gal expression. In contrast, serum a-Gal levels comparable to those of naive mice were observed in mMT mice despite the presence of robust CTL activity against Cap, indicating that preexisting Cap-specific CTLs did not have any effect on the magnitude and duration of transgene expression. The same strategy was used to assess the impact of CTLs against the a-Gal transgene product on AAV-mediated gene delivery and persistence of transgene expression. Preimmunization of mMT mice with an Ad=a-Gal vector induced a robust CTL response to a-Gal. When these mice were injected with AAV2=a-Gal vector, initial levels of a-Gal expression were reduced by more than 1 log and became undetectable by 2 weeks postinjection. Overall, our results indicate that CTLs against the transgene product as opposed to AAV capsid protein are more likely to interfere with AAV transgene expression.

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AAV8‐mediated expression of glucocerebrosidase ameliorates the storage pathology in the visceral organs of a mouse model of Gaucher disease

Abstract: These data demonstrate the effectiveness of AAV-mediated gene therapy at preventing and correcting the biochemical and pathological abnormalities in a Gaucher mouse model, and thus support the continued consideration of this vector as an alternative approach to treating Gaucher disease.

Cited by 58 publications

References 51 publications

Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease

Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease

Distinct immune responses to transgene products from rAAV1 and rAAV8 vectors

Cytotoxic T Lymphocyte Responses to Transgene Product, Not Adeno-Associated Viral Capsid Protein, Limit Transgene Expression in Mice

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