Secretion of a TNFR:Fc Fusion Protein following Pulmonary Administration of Pseudotyped Adeno-Associated Virus Vectors

Sandalon, Ziv; Bruckheimer, Elizabeth; Lustig, Kurt; Rogers, Linda C.; Peluso, Richard W.; Burstein, Haim

doi:10.1128/jvi.78.22.12355-12365.2004

Cited by 29 publications

(21 citation statements)

References 53 publications

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“…49 The specific AAV vector serotypes used in this study contain each AAV serotype 1, 2, 3, 4, 5, 6, 7, and 8 viral capsid and a singlestranded DNA containing the LacZ gene cDNA driven by a CMV immediate-early promoter/enhancer, a hybrid intron, and a bovine growth hormone poly-adenylation …”

Section: Vectorsmentioning

confidence: 99%

Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo

et al. 2007

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Recombinant adeno-associated (AAV) viruses have unique properties, which make them ideal vectors for gene transfer targeting the myocardium. Numerous serotypes of AAV have been identified with variable tropisms towards cardiac tissue. In the present study, we investigated the time course of expression of eight different AAV serotypes in rat myocardium and the nature of the immunity against these serotypes. We first assessed whether neutralizing antibodies (NAb) were present for any of the serotype in the rats. We injected 100 ml of each AAV 1-8 serotype (10 12 DNAse resistant particles/ml), encoding LacZ gene, into the apical wall of rat myocardium. At 1, 4, 12 and 24 weeks after gene delivery, the animals were killed and b-galactosidase (b-gal) activity was assessed by luminometry. Additionally, LacZ genomic copies and AAV capsids copies were measured through standard polymerase chain reaction analysis and cryosections from the area of viral injection were stained for X-gal detection at the same time points. No NAbs were detected against any of AAV serotypes. At all the time points studied, AAV1, 6 and 8 demonstrated the highest efficiency in transducing rat hearts in vivo. Parallel to the results with b-gal activity, the highest levels LacZ and AAV DNA genomic copies were with AAV1, 6 and 8. The positive X-gal staining depicted by these serotypes confirmed these results. These results indicate that among the various AAV serotypes, AAV1, 6 and 8 have differential tropism for the heart unaffected by pre-existing NAb in the rat. Although AAV 1 and 6 vectors induced rapid and robust expression and reach a plateau at 4 weeks, AAV 8 continued increasing until the end of the study. AAV 2, 5 and 7 vectors were slower to induce expression of the reporter gene, but did reach levels of expression comparable to AAV1 and AAV6 vectors after 3 months. Gene Therapy (2007) 14, 989-997.

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Section: Vectorsmentioning

confidence: 99%

Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo

et al. 2007

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“…Recombinant AAV vectors were produced by a standard calcium phosphate transfection method in HEK 293 cells by using the Ad helper, transpackaging, and AAV shuttle plasmids as described (20). Vector titers were determined by realtime PCR and were between 5 and 20 ϫ 10 12 DNase-resistant particles per ml.…”

Section: Methodsmentioning

confidence: 99%

Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: Implications for the therapeutic development of RNAi

McBride¹,

Boudreau²,

Harper³

et al. 2008

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

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551

570

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Huntington's disease (HD) is a fatal, dominant neurodegenerative disease caused by a polyglutamine repeat expansion in exon 1 of the HD gene, which encodes the huntingtin protein. We and others have shown that RNAi is a candidate therapy for HD because expression of inhibitory RNAs targeting mutant human HD transgenes improved neuropathology and behavioral deficits in HD mouse models. Here, we developed shRNAs targeting conserved sequences in human HD and mouse HD homolog (HDh) mRNAs to initiate preclinical testing in a knockin mouse model of HD. We screened 35 shRNAs in vitro and subsequently narrowed our focus to three candidates for in vivo testing. Unexpectedly, two active shRNAs induced significant neurotoxicity in mouse striatum, although HDh mRNA expression was reduced to similar levels by all three. Additionally, a control shRNA containing mismatches also induced toxicity, although it did not reduce HDh mRNA expression. Interestingly, the toxic shRNAs generated higher antisense RNA levels, compared with the nontoxic shRNA. These results demonstrate that the robust levels of antisense RNAs emerging from shRNA expression systems can be problematic in the mouse brain. Importantly, when sequences that were toxic in the context of shRNAs were placed into artificial microRNA (miRNA) expression systems, molecular and neuropathological readouts of neurotoxicity were significantly attenuated without compromising mouse HDh silencing efficacy. Thus, miRNA-based approaches may provide more appropriate biological tools for expressing inhibitory RNAs in the brain, the implications of which are crucial to the development of RNAi for both basic biological and therapeutic applications.gene therapy ͉ Huntington's disease ͉ RNAi ͉ AAV

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“…3 In comparison with the prototypic AAV2, AAV vectors pseudotyped with other serotypes show superior transduction efficiency in various tissues: AAV1 in muscle, 4 pancreatic islets, 5 heart, 6 vascular endothelium, 7 brain and central nervous system (CNS), 8,9 and liver 10 ; AAV3 in Cochlear inner hair cells 11 ; AAV4 in brain 12 ; AAV5 in brain and CNS, 8,13 lung, [14][15][16] eye, 17,18 arthritic joints, 19 and liver 20 ; AAV6 in muscle, 21,22 heart, 23 and airway epithelium 24 ; AAV7 in muscle 4 ; and AAV8 in muscle, 4,25 pancreas, 26 heart, 25 and liver. [27][28][29][30][31] The tissue tropism of different AAV serotypes may permit targeting of AAV vectors to human disease.…”

Section: Introductionmentioning

confidence: 99%

Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs

Jiang¹,

Lillicrap²,

Patarroyo-White³

et al. 2006

Blood

184

159

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IntroductionHemophilia A, a congenital deficiency or dysfunction of factor VIII (FVIII), is the most common severe inherited bleeding disorder in humans. Severe hemophilia A patients have less than 1% of normal FVIII activity, and suffer from spontaneous or traumatic joint and muscle hemorrhage, leading to a chronic painful and disabling arthropathy. Bleeding into body cavities or the brain can result in significant morbidity and mortality if not treated aggressively. 1 Current treatment in the developed world, FVIII protein replacement, has established that restoring circulating FVIII levels above 1% of normal prevents most spontaneous bleeding, and levels above 5% are sufficient to improve the disease from a severe to a mild form. However, the limited worldwide supplies of both plasma-derived and recombinant FVIII, its short half-life in vivo (ϳ 12 hours), and the high cost of treatment (Ͼ $150 000 per year) make gene therapy an attractive alternative to better manage and cure the disease.Previously, we have shown that gene therapy with an AAV2 vector encoding a B-domain-deleted (BDD) canine FVIII (cFVIII) cDNA under the control of a liver-specific promoter resulted in an average of 2% to 3% of normal canine FVIII activity in 2 hemophilia A dogs, 2 providing preliminary support for the feasibility of this approach in humans. In order to further improve the efficacy of liver-targeted AAV-cFVIII, we explored the possibility of using alternative serotypes of AAV. We also assessed the duration of therapeutic benefit following a single injection of AAV-cFVIII in hemophilia A dogs.Since the isolation of AAV2, many different AAV serotypes have been isolated from human and nonhuman primate tissues. 3 In comparison with the prototypic AAV2, AAV vectors pseudotyped with other serotypes show superior transduction efficiency in various tissues: AAV1 in muscle, 4 pancreatic islets, 5 heart, 6 vascular endothelium, 7 brain and central nervous system (CNS), 8,9 and liver 10 ; AAV3 in Cochlear inner hair cells 11 ; AAV4 in brain 12 ; AAV5 in brain and CNS, 8,13 lung, 14-16 eye, 17,18 arthritic joints, 19 and liver 20 ; AAV6 in muscle, 21,22 heart, 23 and airway epithelium 24 ; AAV7 in muscle 4 ; and AAV8 in muscle, 4,25 pancreas, 26 heart, 25 and liver. [27][28][29][30][31] The tissue tropism of different AAV serotypes may permit targeting of AAV vectors to human disease. However, as most of these tissue-specific tropisms have been reported in the rodent, it is important to evaluate cross-species fidelity of differential targeting among serotypes in larger animal modelsIn this report, we have compared the efficacy, gene transfer efficiency, and biodistribution of AAV-cFVIII vectors of serotypes 2, 5, 6, and 8 delivered by portal-vein injection in hemophilia A mice. Furthermore, since prior studies have demonstrated that the hemophilia dog model, compared with the mouse model, more accurately predicts the therapeutic outcomes in humans and other primates, 32,33 we have determined the long-term efficacy and safety of AAV2-cFVI...

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Secretion of a TNFR:Fc Fusion Protein following Pulmonary Administration of Pseudotyped Adeno-Associated Virus Vectors

Cited by 29 publications

References 53 publications

Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo

Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo

Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: Implications for the therapeutic development of RNAi

Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs

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