Intra-articular delivery of a herpes simplex virus IL-1Ra gene vector reduces inflammation in a rabbit model of arthritis

Oligino, Thomas; Ghivizzani, Steven C.; Wolfe, Darren; Lechman, Eric R.; Krisky, David; Zhang, Mi; Evans, Christopher H.; Robbins, Paul D.; Glorioso, Joseph C.

doi:10.1038/sj.gt.3301014

Cited by 109 publications

(57 citation statements)

References 27 publications

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“…However, because of the dense cartilage ECM that surrounds these cells, they have been typically unavailable for genetic modification by direct intraarticular injection of most recombinant vectors. 33,[40][41][42] There have been reports of AAV-mediated transduction of chondrocytes in cartilage explants in culture, [43][44][45] which has been attributed to the smaller size of the AAV particle relative to other viral systems. However, since AAV does not specifically target chondrocytes following direct injection into the joint, it will similarly transduce receptive cells in the synovium.…”

Section: Chondrocytes As Targets For Gene Deliverymentioning

confidence: 99%

Gene-based approaches for the repair of articular cartilage

2004

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Section: Chondrocytes As Targets For Gene Deliverymentioning

confidence: 99%

Gene-based approaches for the repair of articular cartilage

2004

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“…HSV-based vectors have been used successfully in experimental animals to treat nonneoplastic conditions like neurodegenerative diseases, 29 intractable pain 30 and arthritis. 31 The TK gene has been deleted from most of the HSV vectors used for non-neoplastic applications. TK deletion, however, was only a step in the strategy adopted for the construction of the vector, and reintroduction of the TK gene is not inconceivable.…”

Section: Discussionmentioning

confidence: 99%

Lack of enantioselectivity of herpes virus thymidine kinase allows safer imaging of gene delivery

et al. 2003

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Herpes simplex virus thymidine kinase (HSV-TK) is widely used in gene therapy. The enzymatic activity of HSV-TK may be traced in vivo by specific radiopharmaceuticals in order to image transgene expression. However, most of these radiopharmaceuticals are toxic per se or after activation by HSV-TK, and therefore do not represent ideal molecules for clinical applications and repeated imaging. Unlike human cytosolic TK, HSV-TK is not enantioselective and can efficiently phosphorylate both D and L enantiomers of b-thymidine. Here we show that, after phosphorylation by HSV-TK, tritiated L-b-thymidine (LT) is selectively retained inside the cells in vitro and in vivo. We used the in vivo accumulation of radioactive phosphorylated LT to image the HSV-TK-positive cells inside a transplantable murine brain tumour after inoculation of cells producing retroviruses carrying HSV-TK. Owing to their unnatural enantiomeric conformation, phosphorylated LT metabolites are very poorly processed by mammalian enzymes, thus leading to increased cellular retention and minimal toxicity. The ability to image cells expressing the HSV-TK gene by using radiolabelled LT, without damaging the cells accumulating the phosphorylated L-nucleoside, will be important to monitor the levels and spatial distribution of therapeutic vectors carrying HSV-TK.

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“…injection of replication-deficient HSV, transgene expression was detected in synovial fluid for at least 7 days, and therapeutic effect was observed in an IL-1-induced rabbit knee inflammation model when the encoded transgene was interleukin-1 receptor antagonist (IL-1Ra). 65 Delivery of HSV vector to the abrased foot pad of mice or rats resulted in transgene expression in dorsal root ganglion indicating appropriate gene delivery. 66,67 When the transgene encoded was preproenkephalin A precursor protein (PAPP), increased enkephalin synthesis was detected in sensory neurones.…”

Section: Adeno-associated Virusmentioning

confidence: 99%