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A preclinical assessment of the safety and biodistribution of an adenoviral vector containing the herpes simplex virus thymidine kinase gene (Cerepro®) after intracerebral administration
Author(s) -
Langford Gillian,
Dayan Anthony,
YlaHerttuala Seppo,
Eckland David
Publication year - 2009
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1328
Subject(s) - thymidine kinase , biodistribution , spleen , herpes simplex virus , intraperitoneal injection , medicine , ganciclovir , pharmacology , virology , virus , microbiology and biotechnology , immunology , biology , human cytomegalovirus , in vivo
Background Cerepro® (sitimagene ceradenovec) is an adenoviral vector containing herpes simplex virus thymidine kinase gene (HSV‐tk), which is being developed for the treatment of high‐grade glioma with oral ganciclovir (GCV). The nonclinical safety and biodistribution of Cerepro® were assessed following intravenous (i.v.) or intracerebral (i.c.) injection. Methods Crl : WI(GLX/BRL/Han) rats ( n = 198) were injected i.c. or i.v. with Cerepro® or vehicle control, with GCV by intraperitoneal (i.p.) injection to selected groups. Safety was assessed by observation of animal behaviour and post mortem histology. Antibody response was assessed, and biodistribution measured using the quantitative polymerase chain reaction (PCR) and reverse transcriptase‐PCR in blood and tissues. Results Following i.v. or i.c. injection, there was no antibody response and no effect on behaviour, body weight, food consumption or haematological and clinical chemistry parameters. Minor needle track changes were observed in control and Cerepro®‐i.c. injection groups. Transient myeloid hyperplasia was observed in five of the 24 animals in the i.v. injection group and spleen weight increased in both the i.c. and i.v. groups. Cerepro® was detected in the brain and at low levels in blood and spleen following i.c. injection, decreasing with time. Following i.v. injection, Cerepro® was detected in viscera and blood, decreasing with time. Transcription of Cerepro® was detected in the brain following i.c. injection, with lower levels in spleen; following i.v. injection, transcription was seen in viscera. Germline integration was not seen. Conclusions Intracerebral injection of Cerepro® is safe and produces a high level of transgene expression in the brain, with limited biodistribution. Copyright © 2009 John Wiley & Sons, Ltd.