Inflammatory responses and their impact on β-galactosidase transgene expression following adenovirus vector delivery to the primate caudate nucleus

Lawrence, Matthew S.; Foellmer, Harald G.; Elsworth, John D.; Kim, J H; Léránth, Csaba; Kozlowski, Dorothy A.; Bothwell, Alfred L.M.; Davidson, Beverly L.; Bohn, Martha C.; Redmond, D. Eugene

doi:10.1038/sj.gt.3300958

Cited by 50 publications

(18 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…27 Comparable problems were observed during adenovirusmediated gene transfer to the CNS of rhesus monkeys: transgene expression was variable and declined over time, 28,29 in part due to inflammatory responses to adenovirus-transduced cells. 30 Vectors derived from adeno-associated viruses (AAV) elicit little, if any, damage or inflammatory response after intracerebral injection, and may deliver long-term transgene expression to non-dividing cells in multiple tissues, including the brain in rodents and in monkeys. [31][32][33][34][35][36][37][38] However, the size of the transgene inserted must be smaller than 4 kb.…”

Section: Discussionmentioning

confidence: 99%

“…For AAV vectors, transduced cells numbered from 444 400 at 8 weeks to 1 296 350 at 3 years, 32 for lentiviral vectors, 764 149 at 1 month for lentiviral vectors 42 titers ranging between 2.75Â10 12 genome copies per ml for AAV2/1, 1.69Â10 13 42 and between 2Â10 10 PFU ml À1 (ref. 30) and 2Â10 9 PFU ml À1 (ref. 29) for adenoviral vectors.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Gene transfer to the rhesus monkey brain using SV40-derived vectors is durable and safe

et al. 2011

View full text Add to dashboard Cite

Gene transfer to central nervous system (CNS) has been approached using various vectors. Recombinant SV40-derived vectors (rSV40s) transduce human neurons and microglia effectively in vitro and in rodent brains in vivo, so we tested rSV40s gene transfer to rhesus monkey CNS in vivo, to characterize the distribution, duration and safety of such gene delivery. We used rSV40s carrying HIV-1 RevM10 with a carboxyl-terminal AU1 epitope tag as a marker, and others with the antioxidant enzymes, Cu/Zn superoxide dismutase and glutathione peroxidase. Vectors were injected stereotaxically into the caudate nucleus. Transgene expression was studied at 1 and 6 months by immunostaining serial brain sections. After intraparenchymal administration, numerous transgene-expressing cells were seen, with a longitudinal extent of 20 mm. In neurons and, more rarely, microglial cells, transgene expression remained strong throughout the 6-month study period. Astrocytes and oligodendroglia were not transduced. No evidence of inflammation or tissue damage was observed. SV40-derived vectors may thus be useful for long-term gene expression in the monkey brain and, potentially, in the human brain.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gene transfer to the rhesus monkey brain using SV40-derived vectors is durable and safe

et al. 2011

View full text Add to dashboard Cite

show abstract

“…In spite of the supposed immune privilege of the brain, inflammation was also reported following intracerebral injection of first generation viruses. As well as local activation of astrocytes and microglia there was also expression of major histocompatibility antigens T cell activation [6,7,24,31].…”

Section: Discussionmentioning

confidence: 99%

“…Several groups have demonstrated that pre-delivery of GDNF into rat brain using an adenoviral vector, prior to a 6-hydroxydopamine (6-OHDA) lesion can dramatically reduce the cell loss and/or behavioral deficits induced by the lesion [1,3,14,25]. Similar studies using adeno-associated viruses also report sparing of dopamine neurones from the toxin [6,13,22,24,31]. 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].…”

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

View full text Add to dashboard Cite

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.

show abstract

“…In vivo injection into many different tissues has revealed immunogenic responses leading to the loss of gene expression within 4-6 weeks of delivery. [11][12][13][14] Furthermore, in vitro experiments have also identified important limitations with the use of these vectors. 2,15 First, titres must be carefully controlled because excessive levels result in nuclear degeneration followed by loss of viability.…”

Section: Introductionmentioning

confidence: 99%

Helper-dependent adenovirus vectors: their use as a gene delivery system to neurons

et al. 2000

View full text Add to dashboard Cite

Recombinant adenovirus vectors have provided a major advance in gene delivery systems for post-mitotic neurons. However, the use of these first generation vectors has been limited due to the onset of virally mediated effects on cellular function and viability. In the present study we have used primary cultures of cerebellar granule neurons to examine the efficacy and cytotoxic effects of a helper-dependent adenovirus vector (hdAd) in comparison with a first generation vector. Our results demonstrate that the hdAd system provides equally efficient infectivity with significantly reduced toxicity in comparison to first generation vectors. Neurons transduced with a high titre of a first generation vector exhibited a time-dependent shut down in global protein synthesis and impaired physiological function as demonstrated by a

show abstract

Inflammatory responses and their impact on β-galactosidase transgene expression following adenovirus vector delivery to the primate caudate nucleus

Cited by 50 publications

References 45 publications

Gene transfer to the rhesus monkey brain using SV40-derived vectors is durable and safe

Gene transfer to the rhesus monkey brain using SV40-derived vectors is durable and safe

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

Helper-dependent adenovirus vectors: their use as a gene delivery system to neurons

Contact Info

Product

Resources

About