Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy

Jooss, Karin; Chirmule, Narendra

doi:10.1038/sj.gt.3302037

Cited by 248 publications

(155 citation statements)

References 77 publications

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“…13,14 They also cause no detected toxicity and minimal immune responses in transduced regions. 15,16 Moreover, AAV vectors are FDA (Food and Drug Administration) approved and are currently being used in clinical trials. 14 Numerous studies have shown that recombinant AAV with newer serotypes have improved gene transfer into the brain.…”

Section: Introductionmentioning

confidence: 99%

AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

Zhao

et al. 2009

Gene Ther

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We have recently shown that intrastriatal injection of recombinant human erythropoietin (EPO) protects dopaminergic (DA) neurons in the substantia nigra (SN) from 6-hydroxydopamine (6-OHDA) toxicity in a rat model of Parkinson's disease. However, systemic administration of EPO did not protect nigral DA neurons, suggesting that the blood-brain barrier limits the passage of EPO protein into the brain. In the present study, we used an adenoassociated viral (AAV) serotype 9 (AAV9) vector to deliver the human EPO gene into the brain of 6-OHDA-lesioned rats. We observed that expression of the human EPO gene was robust and stable in the striatum and the SN for up to 10 weeks. EPO-immunoreactive (IR) cells were widespread throughout the injected striatum, and EPO-IR neurons and fibers were also found in the ipsilateral SN. Enzyme-linked immunosorbent assay and western blot analyses exhibited dramatic levels of EPO protein in the injected striatum. As a result, nigral DA neurons were protected against 6-OHDA-induced toxicity. Amphetamine-induced rotational asymmetry and spontaneous forelimb use asymmetry were both attenuated. Interestingly, we also observed that intrastriatal injection of AAV9-EPO vectors led to increased numbers of red blood cells in peripheral blood. This highlights the importance of using an inducible gene delivery system for EPO gene delivery.

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Section: Introductionmentioning

confidence: 99%

AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

Zhao

et al. 2009

Gene Ther

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“…The most widely used vectors for gene delivery are genetically engineered viruses, because they, in the long-term evolution of nature, are equipped with specific machineries that facilitate DNA transport into the nucleus of cells (Baranowski et al, 2001). However, a main drawback of viral vectors is the toxicity caused by undesirable acute immune response to viral proteins (Brown and Lillicrap, 2002;Bowers et al, 2003;Chen et al, 2003;Jooss and Chirmule, 2003;Lowenstein, 2003). Moreover, proteins from transgene expression may also exert adverse effects on normal cells either directly or indirectly through conversion of prodrugs to cytotoxic agents (Freeman et al, 1993;Rosenfeld et al, 1995;Alvarez and Curiel, 1997;Pope et al, 1997;Chada et al, 2003).…”

mentioning

confidence: 99%

Characterisation of systemic dissemination of nonreplicating adenoviral vectors from tumours in local gene delivery

Wang

Yang

et al. 2005

Br J Cancer

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Systemic virus dissemination is a potential problem during local gene delivery in solid tumours. However, the kinetics and pathways of the dissemination have not been well characterised during the first 24 h after the infusion is started. To this end, we infused adenoviral vectors for luciferase or enhanced green fluorescence protein into three different tumour models in mice. During and/or after the infusion, we determined the amount of adenoviruses in the tumour, blood, and liver, and examined the transgene expression in the liver, lung, blood, and tumour. In addition, we intravenously injected tumour cells expressing luciferase and examined the biodistribution of these cells in the body. We observed transgene expression in the liver and tumour at 24 h after the infusion, but could not detect transgene expression in the blood and lung. The peak concentration of viral vectors in the plasma occurred during the intratumoral infusion. At 10 min after the infusion, few viral vectors remained in the blood and the ratio of copy numbers of adenoviruses between liver and tumour was 42 in 80% and X10 in 40% of the mice. Most tumour cells injected intravenously accumulated in the lung within the first 24 h. Taken together, these data indicated that systemic virus dissemination occurred mainly during the first 10 min after the intratumoral infusion was started, and that the dissemination was due to infusion-induced convective transport of viral vectors into leaky tumour microvessels.

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“…In order to overcome this second generation vectors were designed containing additional deletions of the E2 (primarily), and E3 or E4 regions of the genome [19]. These vectors not only attenuated the host immune response but had the added advantage of a larger carrying capacity for introduced transgenes [2,18]. More recently, so-called "gutless" adenoviral vectors have been developed which contain no viral coding sequences and display much reduced levels of immunogenicity in vivo [20].…”

Section: Discussionmentioning

confidence: 99%

“…AAV delivery of the dopamine synthetic genes tyrosine hydroxylase (TH), aromatic amino-decarboxylase (AADC) and GTP cyclohydrolase 1(GCH1) has also been successful [2,7,19,32]. Lentiviral vectors have been used for direct delivery of GDNF or the GDNF-related protein, neublastin, into the brain and have proved protective against the effects of a 6-OHDA lesion in rats [18,20], and in primates [21,23,29]. And in a therapy aimed at restoring dopamine function following a 6-OHDA lesion, a lentivirus containing the gene for was able to reduce functional recovery in rats [4].…”

Section: Introductionmentioning

confidence: 99%

In vivo transgene expression from an adenoviral vector is altered following a 6-OHDA lesion of the dopamine system

Torres

Monville

Löwenstein

et al. 2005

Molecular Brain Research

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We have investigated the in vivo dynamics of an adenovirus-based, LacZ expressing vector, RAd36, at different doses, when injected unilaterally into the corpus striatum of normal rats. We have further investigated the characteristics of this vector in the presence of a 6-OHDA lesion of the nigrostriatal pathway. The dopamine-depleting lesion had an effect on both the number and the distribution of cells transduced by the adenoviral vector. The lesioned side of the brain contained significantly greater numbers of β-galactosidase positive cells than the unlesioned side at 3 days, 1 week and 4 weeks post-injection and the distribution of transduced cells was altered by the presence of a dopamine lesion. We conclude that the increased levels of transgene expression seen in the lesioned hemisphere are due to a change in the diffusion characteristics of the injected vector in the lesioned hemisphere. These results indicate that, when investigating the use of virus-based vectors, ultimately for use in gene therapies in the CNS, the in vivo dynamics of the vector need to be assessed not only in the normal brain, but also in the pathological brain state such as animal models of target diseases.

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Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy

Cited by 248 publications

References 77 publications

AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

Characterisation of systemic dissemination of nonreplicating adenoviral vectors from tumours in local gene delivery

In vivo transgene expression from an adenoviral vector is altered following a 6-OHDA lesion of the dopamine system

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