A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency.
Ornithine transcarbamylase deficiency (OTCD) is an inborn error of urea synthesis that has been considered as a model for liver-directed gene therapy. Current treatment has failed to avert a high mortality or morbidity from hyperammonemic coma. Restoration of enzyme activity in the liver should suffice to normalize metabolism. An E1- and E4-deleted vector based on adenovirus type 5 and containing human OTC cDNA was infused into the right hepatic artery in adults with partial OTCD. Six cohorts of three or four subjects received 1/2 log-increasing doses of vector from 2 x 10(9) to 6 x 10(11) particles/kg. This paper describes the experience in all but the last subject, who experienced lethal complications. Adverse effects included a flu-like episode and a transient rise in temperature, hepatic transaminases, thrombocytopenia, and hypophosphatemia. Humoral responses to the vector were seen in all research subjects and a proliferative cellular response to the vector developed in apparently naive subjects. In situ hybridization studies showed transgene expression in hepatocytes of 7 of 17 subjects. Three of 11 subjects with symptoms related to OTCD showed modest increases in urea cycle metabolic activity that were not statistically significant. The low levels of gene transfer detected in this trial suggest that at the doses tested, significant metabolic correction did not occur.
Raper
Steven E
SE
Institute for Human Gene Therapy and Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
Yudkoff
Marc
M
Chirmule
Narendra
N
Gao
Guang-Ping
GP
Nunes
Fred
F
Haskal
Ziv J
ZJ
Furth
Emma E
EE
Propert
Kathleen J
KJ
Robinson
Michael B
MB
Magosin
Susan
S
Simoes
Heather
H
Speicher
Lisa
L
Hughes
Joseph
J
Tazelaar
John
J
Wivel
Nelson A
NA
Wilson
James M
JM
Batshaw
Mark L
ML
D000260:Adenoviruses, Human / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000097:blood; D000641:Ammonia / Q000097:blood; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use*; D006579:Heterozygote; D006801:Humans; D017403:In Situ Hybridization; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009954:Ornithine Carbamoyltransferase / Q000235:genetics* / Q000378:metabolism; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000201:enzymology / Q000628:therapy*; D009963:Orotic Acid / Q000652:urine; D010865:Pilot Projects; D012449:Safety
D000596:Amino Acids; D009963:Orotic Acid; D000641:Ammonia; D009954:Ornithine Carbamoyltransferase