Bioavailability, biodistribution, and CNS toxicity of clinical-grade parvovirus H1 after intravenous and intracerebral injection in rats.
The autonomous parvovirus H1 (H1PV) is transmitted in rodent populations. The natural host is the rat, in which H1PV infection is pathogenic only in fetuses and newborns. H1PV infection of human cancer cells leads to strong oncolytic effects in preclinical models. In preparation for a clinical trial of H1PV injection in patients with malignant brain tumors, H1PV had to be prepared to Good Manufacturing Practice standards, including extensive toxicology testing in rats. Because the trial involves direct intracerebral injection of H1PV into the tumor and around the resection cavity, possible toxicity to CNS tissue had to be investigated. In addition, quantitative blood levels and the tissue distribution of H1PV after single intracerebral or intravenous injection were measured. Direct injection of H1PV into rat brain at 3 dose levels (maximum, 7.96 × 107 pfu) did not cause any macroscopic or histologic pathology. Furthermore, H1PV infection of the brain did not alter central or autonomous nervous system function. H1PV DNA was detected in almost all organs at 6 h, 48 h, and 14 d after intravenous and intracerebral injection, with the highest levels in liver and spleen. H1PV concentrations in most organs were similar after intravenous and intracerebral injection, indicating high permeability of the blood-brain barrier for this small virus. The current results demonstrate wide organ distribution of H1PV after intravenous or intracerebral injection, confirm that H1PV is nonpathogenic in adult rats even after direct injection into the brain, and form the basis for the ongoing ParvOryx01 clinical trial.
Department of Neurosurgery, University Hospital, Heidelberg, Germany, Department of Applied Tumor Virology, German Cancer Research Center, Heidelberg, Germany. kgeletneky@med.uni-heidelberg.de.
Karsten
K
Geletneky
BSL BIOSERVICE Scientific Laboratories GmbH, Planegg/Munich, Germany.
Anne-Laure
AL
Leoni
KALEIDIS Consultancy in Histopathology, Saint-Louis, France.
Gabriele
G
Pohlmeyer-Esch
BSL BIOSERVICE Scientific Laboratories GmbH, Planegg/Munich, Germany.
Stephanie
S
Loebhard
Department of Applied Tumor Virology, German Cancer Research Center, Heidelberg, Germany.
Barbara
B
Leuchs
DMPKORE, Ingolstadt, Germany.
Constance
C
Hoefer
IASON Consulting, Niederzier, Germany.
Karin
K
Jochims
ORYX GmbH and Co KG, Baldham, Germany.
Michael
M
Dahm
ORYX GmbH and Co KG, Baldham, Germany.
Bernard
B
Huber
Department of Applied Tumor Virology, German Cancer Research Center, Heidelberg, Germany.
Jean
J
Rommelaere
ORYX GmbH and Co KG, Baldham, Germany.
Ottheinz
O
Krebs
Coordination Center for Clinical Trials, University Hospital, Heidelberg, Germany.
Jacek
J
Hajda
D000818:Animals; D001682:Biological Availability; D002490:Central Nervous System / Q000473:pathology / Q000821:virology*; D004279:DNA, Viral / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D052661:H-1 parvovirus / Q000472:pathogenicity*; D007275:Injections, Intravenous; D008099:Liver / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods* / Q000592:standards; D051381:Rats; D013154:Spleen / Q000821:virology; D013997:Time Factors; D019562:Viral Load
D004279:DNA, Viral