Intravenous administration of recombinant adenoviruses causes thrombocytopenia, anemia and erythroblastosis in rabbits.
BACKGROUND
Recombinant adenoviruses are highly efficient gene transfer vehicles but their administration to mammals is accompanied by a strong inflammatory response. The present study reports additional side effects observed during adenoviral gene transfer studies in rabbits.


METHODS
Hematological and serological parameters, the course of viremia and the organ distribution were analyzed after in vivo administration of E1-deleted adenoviruses in rabbits.


RESULTS
The systemic administration of a therapeutic dose of 5 x 10(11) infectious particles/kg (infusion time 20 min) led to an average reduction of 80-90% in the platelet count within 48 h. Full recovery took 10-14 days. Virus administration induced a strong but transient erythroblastosis (peaking 24 h after administration) which settled 48 h later. Normochromic anemia occurred over the next 10 days with hemoglobin levels dropping by about 40% to reach the lowest level 10 days after administration and taking two months for full recovery. Dose-dependent thrombocytopenia was also found in mice, but neither erythroblastosis nor anemia was observed (in equivalent doses). The hematological findings did not improve after local injection via the portal vein. Local and systemic administration led to a comparable course of viremia. Only minor differences were found in the biodistribution of viruses between local and systemic administration. Large amounts of viral DNA and transgene expression were found in the lungs, the kidneys and the ovaries, even after local administration via the portal vein.


CONCLUSIONS
Local intravenous injection via the portal vein does not prevent systemic spread of viral vectors and the occurrence of vector-related side effects. The hematological changes observed in rabbits suggest the need for careful monitoring of hematological and rheological parameters in clinical trials.
Cichon
G
G
Department of Molecular Cell Biology, Humboldt University Berlin, Max-Delbrück Center for Molecular Medicine, Berlin-Buch, Germany. GCichon@mdc-berlin.de
Schmidt
H H
HH
Benhidjeb
T
T
Löser
P
P
Ziemer
S
S
Haas
R
R
Grewe
N
N
Schnieders
F
F
Heeren
J
J
Manns
M P
MP
Schlag
P M
PM
Strauss
M
M
D000256:Adenoviridae / Q000235:genetics* / Q000472:pathogenicity*; D000740:Anemia / Q000209:etiology*; D000818:Animals; D004900:Erythroblasts / Q000473:pathology*; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors; D007275:Injections, Intravenous; D007763:Lac Operon; D051379:Mice; D011169:Portal Vein; D011817:Rabbits; D011995:Recombination, Genetic; D013921:Thrombocytopenia / Q000209:etiology*; D013997:Time Factors; D014018:Tissue Distribution