Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy

Niemeyer, Glenn P.; Herzog, Roland W.; Mount, Jane D.; Arruda, Valder R.; Tillson, D. Michael; Hathcock, John T.; Ginkel, Frederik W. van; High, Katherine A.; Lothrop, Clinton D.

doi:10.1182/blood-2008-10-181479

Cited by 250 publications

(186 citation statements)

References 45 publications

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“…[7][8][9] There are studies following the transgene expression and effects in the long-term. [10][11][12] However, not much is known about the expression of angiogenic growth factors delivered by AAV in large animal models. Previously, the effects of AAV vascular endothelial growth factor A (AAV-VEGF-A) on angiogenesis in ischemic skeletal muscle have been primarily evaluated in small animal models for time points no longer than 6 months.…”

Section: Introductionmentioning

confidence: 99%

Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle

et al. 2011

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Section: Introductionmentioning

confidence: 99%

Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle

et al. 2011

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“…[12][13][14] We did not observe tumour formation in any of the rats that received the rAAV injections (data not shown). For more information regarding tumour formation, further studies are needed by using methods such as Northern blotting, integration site analysis 26 and oncogene analysis.…”

Section: Discussionmentioning

confidence: 99%

Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy

et al. 2010

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We had previously reported that transduction of the channelrhodopsin-2 (ChR2) gene into retinal ganglion cells restores visual function in genetically blind, dystrophic Royal College of Surgeons (RCS) rats. In this study, we attempted to reveal the safety and influence of exogenous ChR2 gene expression. Adeno-associated virus (AAV) type 2 encoding ChR2 fused to Venus (rAAV-ChR2V) was administered by intra-vitreous injection to dystrophic RCS rats. However, rAAV-ChR2 gene expression was detected in non-target organs (intestine, lung and heart) in some cases. ChR2 function, monitored by recording visually evoked potentials, was stable across the observation period (64 weeks). No change in retinal histology and no inflammatory marker of leucocyte adhesion in the retinal vasculature were observed. Although antibodies to rAAV (0.01-12.21 mg ml À1 ) and ChR2 (0-4.77 mg ml À1 ) were detected, their levels were too low for rejection. T-lymphocyte analysis revealed recognition by T cells and a transient inflammation-like immune reaction only until 1 month after the rAAV-ChR2V injection. In conclusion, ChR2, which originates from Chlamydomonas reinhardtii, can be expressed without immunologically harmful reactions in vivo. These findings will help studies of ChR2 gene transfer to restore vision in progressed retinitis pigmentosa.

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“…81,84 Adeno-associated virus (AAV)-mediated liverdirected GT corrected hemophilic dogs without toxicity for more than 8 years whereas in the same experiment, dogs undergoing muscle-directed GT had a bleed frequency similar to untreated hemophilic dogs. 84 Initial clinical data showing the advantages of liver directed expression come from hemophilia clinical trials in which muscle-directed injection of constitutive AAV vectors failed to show adequate therapeutic factor IX levels 85,86 whereas portal vein injections of liver-specific AAV vectors showed some therapeutic efficacy in the highest dose. 7 However, although no immune response was observed against factor IX, its expression decreased to baseline levels by 10 weeks after infusion.…”

Section: Livermentioning

confidence: 98%

“…81 Targeting the liver (hepatocytes) allows not only direct access to the circulation (for systemic delivery) but can also induce tolerance to the transgene that permits longlasting expression. [81][82][83][84] Natural and chimeric promoters and enhancers have been incorporated into viral and nonviral vectors to target expression of factor VIIa, factor VIII or factor IX to hepatocytes. Promoter regions from liver-specific genes such as albumin 40 and human a1 antitrypsin (hAAT) 38 are good examples of natural promoters.…”

Section: Livermentioning

confidence: 99%

Physiological and tissue-specific vectors for treatment of inherited diseases

Toscano

Romero

Muñoz³

et al. 2010

Gene Ther

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After more than 1500 gene therapy clinical trials in the past two decades, the overall conclusion is that for gene therapy (GT) to be successful, the vector systems must still be improved in terms of delivery, expression and safety. The recent development of more efficient and stable vector systems has created great expectations for the future of GT. Impressive results were obtained in three primary immunodeficiencies and other inherited diseases such as congenital blindness, adrenoleukodystrophy or junctional epidermolysis bullosa. However, the development of leukemia in five children included in the GT clinical trials for X-linked severe combined immunodeficiency and the silencing of the therapeutic gene in the chronic granulomatous disease clearly showed the importance of improving safety and efficiency. In this review, we focus on the main strategies available to achieve physiological or tissue-specific expression of therapeutic transgenes and discuss the importance of controlling transgene expression to improve safety. We propose that tissue-specific and/or physiological viral vectors offer the best balance between efficiency and safety and will be the tools of choice for future clinical trials in GT of inherited diseases.

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Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy

Cited by 250 publications

References 45 publications

Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle

Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle

Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy

Physiological and tissue-specific vectors for treatment of inherited diseases

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