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.
Thomas S. Deisboeck,Hiroaki Wakimoto,Hiroaki Wakimoto,Ulf Nestler,Ulf Nestler,David N. Louis,P K Sehgal,M Simon,E A Chiocca,Fred H. Hochberg +9 more
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TLDR
The 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 ofHSV-based therapeutic viral vector constructs in the brain.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.read more
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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.
Edyta Tyminski,Stanley LeRoy,Kinya Terada,Dianne M. Finkelstein,Janice L. Hyatt,Mary K. Danks,Philip M. Potter,Yoshinaga Saeki,E. Antonio Chiocca +8 more
TL;DR: A mutant herpes simplex virus type 1 with deletions in the viral UL39 and gamma(1)34 genes and an insertion of the two prodrug activating genes, CYP2B1 and secreted human intestinal carboxylesterase, provides effective multimodal therapy for gliomas in preclinical models when combined with these chemotherapy agents.
Journal ArticleDOI
Gene transfer vector biodistribution: pivotal safety studies in clinical gene therapy development.
P Gonin,C Gaillard +1 more
TL;DR: The importance and pivotal role of biodistribution study in gene transfer medicine development is shown through the determination of target organs for toxicity, germline transmission assessment and determination of risks of shedding and spreading of vectors in the gene transfer recipient and the environment.
Journal ArticleDOI
Viral Vectors for Neural Circuit Mapping and Recent Advances in Trans-synaptic Anterograde Tracers.
Xiangmin Xu,Todd C. Holmes,Min-Hua Luo,Min-Hua Luo,Kevin T. Beier,Gregory D. Horwitz,Gregory D. Horwitz,Fei Zhao,Wen-Bo Zeng,May Hui,Bert L. Semler,Rozanne M. Sandri-Goldin +11 more
TL;DR: This work provides a primer on currently applied anterograde and retrograde viral tracers with practical guidance on experimental uses, and discusses and highlights key technical and conceptual considerations for developing new safer and more effective anterogsrade trans-synaptic viral vectors for neural circuit analysis in multiple species.
Journal ArticleDOI
Animal models for target diseases in gene therapy--using DNA and siRNA delivery strategies.
Ian S. Blagbrough,Chiara Zara +1 more
TL;DR: A critical appraisal of the recent literature sets out the different models that are currently being investigated to bridge from studies in cell lines through towards clinical reality, and aims for the safe development of clinically effective delivery systems for DNA and RNAi technologies.
Journal ArticleDOI
Safety and biodistribution studies of an HSV multigene vector following intracranial delivery to non-human primates
Darren Wolfe,Ajay Niranjan,Anita M. Trichel,Clayton A. Wiley,Ali Ozuer,E Kanal,Douglas Kondziolka,David Krisky,John A. Goss,Neal A. DeLuca,Michael Murphey-Corb,Joseph C. Glorioso +11 more
TL;DR: It is shown that NUREL-C2, a replication-defective multigene HSV-based vector, is effective in treating animal models of glioma and should be suitable for safety testing in humans.
References
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Attenuated, Replication-Competent Herpes Simplex Virus Type 1 Mutant G207: Safety Evaluation of Intracerebral Injection in Nonhuman Primates
William D. Hunter,Robert L. Martuza,Frank Feigenbaum,Tomoki Todo,Toshihiro Mineta,Takahito Yazaki,Masahiro Toda,Joseph T. Newsome,R. Craig Platenberg,Herbert J. Manz,Samuel D. Rabkin +10 more
TL;DR: It is concluded that intracerebral inoculation of up to 109 PFU of G207, well above the efficacious dose in mouse tumor studies, is safe and therefore appropriate for human clinical trials.
Journal ArticleDOI
In Vivo Behavior of Genetically Engineered Herpes Simplex Viruses R7017 and R7020. II. Studies in Immunocompetent and Immunosuppressed Owl Monkeys (Aotus trivirgatus)
TL;DR: The genetically engineered herpes simplex virus strains R7017 and R7020 were tested in owl monkeys previously shown to model herpetic diseases of immunocompromised patients and neonates and could not be differentiated from irradiated controls with respect to morbidity or mortality.
Journal ArticleDOI
Viral shedding and biodistribution of G207, a multimutated, conditionally replicating herpes simplex virus type 1, after intracerebral inoculation in aotus.
Tomoki Todo,Frank Feigenbaum,Samuel D. Rabkin,Fred D. Lakeman,Joseph T. Newsome,Paul Johnson,Erin Mitchell,Daniel Belliveau,Jeffrey M. Ostrove,Robert L. Martuza +9 more
TL;DR: The results ascertain the safety of G207 in the brain and indicate that strict biohazard management may not be required for G207-treated patients, as early as 21 days postinoculation.
Journal ArticleDOI
Immunization of experimental animals with reconstituted glycoprotein mixtures of herpes simplex virus 1 and 2: protection against challenge with virulent virus.
TL;DR: Artificial mixtures of the glycoproteins B, C, D, and E of herpes simplex virus 1 and 2 were used to immunize mice, guinea pigs, and owl monkeys and suggested low or borderline levels of cellular immunity.
Journal ArticleDOI
High efficiency gene transfer to the central nervous system of rodents and primates using herpes virus vectors lacking functional ICP27 and ICP34.5.
Howard Mk,Kershaw T,B. J. Gibb,Storey N,Storey N,Alasdair Roderick Maclean,Bai-Yun Zeng,Tel Bc,Jenner P,Brown Sm,Clifford J. Woolf,Patrick N. Anderson,Robert S. Coffin,David S. Latchman +13 more
TL;DR: It is reported that viruses lacking functional genes for ICP27 and ICP34.5 can deliver a marker gene to both the rodent and primate CNS with high efficiency whilst producing relatively minimal damage and having no effect on sodium currents in dorsal root ganglion neurons.