Potential and limitations of a γ34.5 mutant of herpes simplex 1 as a gene therapy vector in the CNS

McMenamin, M M; Byrnes, Andrew P.; Pike, F. G.; Charlton, H. M.; Coffin, Robert S.; Latchman, David S.; Wood, Matthew

doi:10.1038/sj.gt.3300639

Cited by 23 publications

(12 citation statements)

References 33 publications

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“…60,61 The distribution pattern reported here is very similar to the one described by McMenamim and co-workers. 62 As expected, expression from the HCMV IE promoter was down-regulated efficiently shortly after delivery, and by day 14 after surgery no transduced cells were detected.…”

Section: Discussionmentioning

confidence: 68%

Latency associated promoter transgene expression in the central nervous system after stereotaxic delivery of replication-defective HSV-1-based vectors

et al. 2001

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The herpes simplex virus type 1 (HSV-1) latency associated promoter (LAP) has been shown to sustain long-term reporter gene expression within sensory neurones. Its activity within the CNS is, however, less well understood. In this study we characterise the activity of the LAP after stereotaxic delivery of recombinant HSV-1-based vectors to the brain. Two classes of vectors were utilised in these studies: (1) a replication-defective vector lacking the glycoprotein H and thymidine kinase genes, designated CS1, and (2) a virus mutant severely impaired for immediate-early (IE) gene expression which lacks functional VP16, ICP4 and ICP0 genes, designated in1388. Both vectors contain the LacZ gene under the control of the LAP. Following delivery of either vector to the striatum, ␤-gal expression was detected within anatomically related CNS regions distal to the site of injection. At these sites the number of ␤-gal-positive cells increased with time and remained stable up to 4 weeks p.i. ␤-Gal expression could not be detected at the site

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Section: Discussionmentioning

confidence: 68%

Latency associated promoter transgene expression in the central nervous system after stereotaxic delivery of replication-defective HSV-1-based vectors

et al. 2001

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“…16 In this study, the feasibility of administering a replicationselective HSV-1 vector by CED into normal brain was therefore examined in detail. In spite of the large number of preclinical studies that have involved the direct intracranial administration of HSV-based vectors, 17,18,[20][21][22][23][24][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] remarkably this represents the first published study to evaluate the distribution properties of an HSV-1 vector using appropriate infusion parameters in both gray and white matter, as well as evaluation of strategies to improve vector distribution.…”

Section: Discussionmentioning

confidence: 99%

“…16 Clearly this has the potential to make the effective intracranial administration of HSV-1-based vectors unachievable. Nevertheless, in addition to the aforementioned clinical trials, [6][7][8][9] HSV vectors have been administered by stereotactic injection into normal mouse, [17][18][19] rat [20][21][22][23][24][25][26] and primate brains, [20][21][22][23][24][25][26][27][28] animal models of high-grade glioma, [29][30][31][32][33][34][35] mucopolysaccharidosis type VII, 36 GM2 gangliosidosis 37 and Parkinson's disease, [37][38][39] as well as being administered by CED into a glioma rat model. 40 In view of there being this large number of studies, it is surprising that to date no attempt has been made to systematically evaluate and optimize the delivery of these vectors directly into the brain.…”

Section: Introductionmentioning

confidence: 99%

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

et al. 2011

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The direct intraparenchymal administration of oncolytic viral vectors by convection-enhanced delivery (CED) represents a promising new treatment strategy for malignant gliomas. However, there is no evidence to suggest that oncolytic viruses as large as herpes simplex virus-1 (HSV-1) can be administered by CED, as this has not been systematically examined in an animal model. In this study, the administration of a herpes simplex viral vector, HSV1, has been evaluated in detail in the gray and white matter of both rat and pig models, using high flow-rate infusions, co-infusing heparin or preinfusing the tissue with an isotonic albumin solution. Rat HSV-1 infusions at both slow (0.5 ml min À1 ) and high infusion rates (2.5 ml min À1 ) led to extensive tissue damage and negligible cell transduction. Co-infusion with heparin led to extensive hemorrhage. Preinfusion of tissue with an isotonic albumin solution facilitated widespread vector distribution and cell transduction in white matter only. Using this approach in pig brain led to widespread vector distribution with extensive transduction of astrocytes and activated microglia. In rat brain, enhanced green fluorescent protein expression peaked 48 h after vector administration and was associated with a vigorous immune response. These findings indicate that direct infusions of HSV-1-based viral vectors into the brain lead to minimal vector distribution, negligible cell transduction and extensive damage. Tissue preinfusion with an isotonic solution prior to vector administration represents an effective technique for achieving widespread HSV-1 distribution.

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“…After i.c. inoculation of R3616 or 1716, virus is widely distributed via retrograde transport in neurons, and there is some expression of viral antigens and possible viral replication within the first week, which then ceases (48,55). In studies using G207 as a helper virus for defective HSV vectors, we found that inoculation in the rat substantia nigra resulted in LacZ expression only in cells surrounding the site of inoculation and not at retrograde sites that were identified by expression of the alkaline phosphatase reporter gene on the defective vector (59).…”

Section: Discussionmentioning

confidence: 99%

Attenuated, Replication-Competent Herpes Simplex Virus Type 1 Mutant G207: Safety Evaluation in Mice

Sundaresan

Hunter

Martuza

et al. 2000

J Virol

137

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Herpes simplex virus type 1 (HSV-1) mutants that are attenuated for neurovirulence are being used for the treatment of cancer. We have examined the safety of G207, a multimutated replication-competent HSV-1 vector, in mice. BALB/c mice inoculated intracerebrally or intracerebroventricularly with 10 7 PFU of G207 survived for over 20 weeks with no apparent symptoms of disease. In contrast, over 80% of animals inoculated intracerebrally with 1.5 ؋ 10 3 PFU of HSV-1 wild-type strain KOS and 50% of animals inoculated intracerebroventricularly with 10 4 PFU of wild-type strain F died within 10 days. Similarly, after intrahepatic inoculation of G207 (3 ؋ 10 7 PFU) all animals survived for over 10 weeks, whereas no animals survived for even 1 week after inoculation with 10 6 PFU of KOS. After intracerebroventricular inoculation, LacZ expression was initially observed in the cells lining the ventricles and subarachnoid space; expression decreased until almost absent within 5 days postinfection, with no apparent loss of ependymal cells. G207 DNA could be detected by PCR in the brains of mice 8 weeks after intracerebral inoculation; however, no infectious virus could be detected after 2 days. As a model for latent HSV in the brain, we used survivors of an intracerebral inoculation of HSV-1 KOS at the 50% lethal dose. Inoculation of a high dose of G207 at the same stereotactic coordinates did not result in reactivation of detectable infectious virus or symptoms of disease. We conclude that G207 is safe at or above doses that were efficacious in mouse tumor studies.Herpes simplex virus type 1 (HSV-1) is a neurotropic DNA virus which infects a wide range of cell types in different animals. Natural infections either follow a lytic, replicative cycle or establish latency. Latency is characterized by the long-term persistence of viral DNA in latently infected neurons, the lack of infectious or replicating virus, the lack of viral gene expression except for the latency-associated transcripts (LATs), and in some situations episodic reactivation of infectious virus (74). In humans, the natural host, HSV-1 causes a number of diseases, including gingivostomatitis and pharyngitis after primary oral-facial infection, recurrent herpes labialis, genital herpes, keratitis after eye infection, disseminated visceral infections in immunocompromised patients, hepatitis, and encephalitis after spread to the central nervous system (CNS) (13).HSV encephalitis is the most common CNS viral infection, occurring in two to three persons per million (13). Brain pathology is usually localized to the temporal lobe and limbic system, with asymmetric necrotizing encephalitis, inflammation, and hemorrhage (19, 33). The majority of cases of encephalitis occur in patients with recurrent HSV who are seropositive at onset of disease. Even with acyclovir therapy, mortality is about 20%, and about 20% of survivors have longterm morbidity, including cognitive abnormalities (23, 51).A number of animal models of HSV encephalitis involving spread from peripheral in...

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Potential and limitations of a γ34.5 mutant of herpes simplex 1 as a gene therapy vector in the CNS

Cited by 23 publications

References 33 publications

Latency associated promoter transgene expression in the central nervous system after stereotaxic delivery of replication-defective HSV-1-based vectors

Latency associated promoter transgene expression in the central nervous system after stereotaxic delivery of replication-defective HSV-1-based vectors

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

Attenuated, Replication-Competent Herpes Simplex Virus Type 1 Mutant G207: Safety Evaluation in Mice

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