Toxicity and biodistribution of a first-generation recombinant adenoviral vector, in the presence of hydroxychloroquine, following retroductal delivery to a single rat submandibular gland.
OBJECTIVE
We examined the toxicity and biodistribution associated with a single administration of a first-generation, serotype 5, adenoviral vector encoding human growth hormone (hGH; AdCMVhGH) to a single rat submandibular gland in the presence of hydroxychloroquine (HCQ). Previously, we showed that hGH is primarily secreted into saliva (approximately ninefold serum level) when expressed as a transgene in salivary glands (e.g. Baum et al, 1999), but administration of HCQ substantially increases the hGH levels secreted into the bloodstream (Hoque et al, 2001). A potential application of this observation is for patients with adult hGH deficiency.


METHODS
Six groups of male and female adult rats (n = 12 each) were studied, with zero to 1.5 x 10(11) particles of AdCMVhGH, +/-HCQ, administered retroductally. Multiple clinical and pathological parameters, as well as vector tissue distribution, were assessed.


RESULTS
All animals survived until the scheduled day of sacrifice, and essentially no untoward events were observed clinically or at gross necropsy. We observed no vector-related effects on clinical hematology evaluations and a single, transient significant change on clinical chemistry evaluations (increased serum globulin levels). Three days after AdCMVhGH administration, the vector distributed to all tissues analyzed with the exception of gonads and heart. By day 29, most organs, other than the targeted and contralateral submandibular glands, were negative for the presence of vector. On day 3, none of the animals tested positive for the presence of replication competent adenovirus in either their blood or saliva.


CONCLUSIONS
Salivary gland delivery of AdCMVhGH +/-HCQ appears associated with limited toxicity in rats.
Zheng
C
C
Gene Therapy and Therapeutics Branch, NIDCR, NIH, DHHS, Bethesda, MD 20892-1190, USA.
Voutetakis
A
A
Kok
M R
MR
Goldsmith
C M
CM
Smith
G B J
GB
Elmore
S
S
Nyska
A
A
Vallant
M
M
Irwin
R D
RD
Baum
B J
BJ
D000256:Adenoviridae / Q000235:genetics*; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000681:Amylases / Q000097:blood; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D005260:Female; D005822:Genetic Vectors / Q000235:genetics*; D019382:Human Growth Hormone / Q000235:genetics* / Q000633:toxicity; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D010957:Plasmids / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins; D012712:Serum Globulins / Q000032:analysis; D013363:Submandibular Gland / Q000187:drug effects / Q000378:metabolism*; D014018:Tissue Distribution; D014779:Virus Replication
D018501:Antirheumatic Agents; D011994:Recombinant Proteins; D012712:Serum Globulins; D019382:Human Growth Hormone; D006886:Hydroxychloroquine; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D000681:Amylases