Development of a novel non-human primate model for preclinical gene vector safety studies. Determining the effects of intracerebral HSV-1 inoculation in the common marmoset: a comparative study

Abstract

The owl monkey (Aotus trivirgatus) has served as the standard non-human primate model of herpes simplex virus-1 (HSV-1) infection because it is highly susceptible to HSV-1 encephalitis. Owl monkeys, however, are expensive, difficult to obtain, and difficult to maintain in captivity, thus greatly hampering the efficiency of preclinical gene therapy trials for brain tumors using HSV-1-based vectors. We have therefore compared the susceptibility of the common marmoset (Callithrix jacchus) with the owl monkey in a model of intracerebral inoculation of wildtype HSV-1 F-strain at increasing titers. The common marmosets consistently succumbed earlier to viral encephalitis than the owl monkeys.The histological evaluation of the common marmoset revealed extensive HSV-1 infection with a concomitant yet less marked inflammatory response compared to the owl monkeys. PCR for HSV-1 demonstrated a similar extra-CNS shedding route in both experimental models. Our findings show that the common marmoset is at least as susceptible to intracerebral HSV-infection as the owl monkey and that it can therefore serve as a valid and reliable experimental model for the important preclinical safety tests of HSV-based therapeutic viral vector constructs in the brain.

Brain Tumor Oncolysis with Replication-Conditional Herpes Simplex Virus Type 1 Expressing the Prodrug-Activating Genes, CYP2B1 and Secreted Human Intestinal Carboxylesterase, in Combination with Cyclophosphamide and Irinotecan

“…However, it is not known if the addition of cyclophosphamide and CPT-11 will produce an increase in overall toxicity. Our findings justify the performance of preclinical toxicity data in appropriate nonhuman primate animal models to determine appropriate dosing and schedule for this triple combination (33).…”

Gene transfer vector biodistribution: pivotal safety studies in clinical gene therapy development

“…Some authors have undertaken biodistribution studies in nonhuman primates on the sole ground that they are the most 'similar' to humans. 17,40 In our opinion, species models should be used in well-defined cases like aotus or marmosets for HSV, 18,59,60 or cotton-rat for AdV. 70 Regarding biodistribution, big species can be justified as well when addressing problems that cannot find solution in smaller mammals (like special administration routes, which Techniques for gene transfer vectors biodistribution P Gonin and C Gaillard S105 cannot be modeled correctly in rodents).…”

“…administration, DISChGMCSF, a gH-deleted HSV-2-based vector expressing human GM-CSF was widely distributed up to day 28, but by day 56 had disappeared from the gonads and brain and was found only in the blood and liver. Local routes (intracerebral 18,59 and intraprostatic) 60 were also investigated.…”

Safety and biodistribution studies of an HSV multigene vector following intracranial delivery to non-human primates

“…32,33 We have carried out preclinical studies in animal models of human brain tumors that suggest highly defective nonreplicating HSV vectors such as NUREL C2 may prove valuable in the treatment of recurrent glioma in patients. 14,23,34 The toxicology and human studies with oncolyotic vectors provide encouraging evidence that HSV can be safely applied to patients and since defective vectors are incapable of productive infection even in tumor cells, it is unlikely that the defective virus platform will itself pose a safety concern. Nevertheless, vector toxicity may vary with the transgene(s) payload, and thus it is essential to establish that the combination Biodistribution of NUREL-C2 after intracranial delivery.…”

“…These findings confirm that virus spread either does not occur or occurs at very low levels by this route of administration and is in agreement with findings reported for oncolytic HSV vectors. 29,30,34 Brain pathology…”