Adenovirus-mediated gene transfer to lower limb artery of patients with chronic critical leg ischemia.
Arterial gene transfer offers a promising new approach for the treatment of vascular disorders. However, no data are available about the gene transfer efficiency in human arteries in vivo. The aim of this study was to evaluate the safety and feasibility of catheter-mediated adenoviral gene transfer in human peripheral arteries. Ten patients (8 females, 2 males, mean age 80 +/- 8 years) suffering from chronic critical leg ischemia with a prior decision for amputation were recruited in the study. Gene transfer was performed in eight patients in conjunction with a conventional percutaneous transluminal angioplasty, using a perfusion coil balloon catheter. Two patients served as controls. Increasing concentrations of replication-deficient adenoviruses (titers from 1 x 10(8) to 4 x 10(10) PFU) containing a nuclear-targeted beta-galactosidase marker gene were administered into the arteries over 10 min via the catheter. Amputations were performed 20 to 51 hr after the procedures and gene transfer efficiency was evaluated in the transduced arteries using X-Gal staining for beta-galactosidase activity. Beta-galactosidase gene transfer was well tolerated and no adverse tissue responses or systemic complications were observed in any of the patients. Gene transfer was successful in six of the eight patients. Gene transfer efficiency varied between 0.04 and 5.0% of all arterial cells. Transgene expression was detected in smooth muscle cells, endothelial cells, and macrophages and in tunica adventitia. However, transgene activity was not evenly distributed in the arterial wall and no transgene activity was found beneath advanced atherosclerotic lesions. The safety and feasibility of in vivo gene transfer by adenoviral vectors to human peripheral arteries were established. Although improvements are still required in gene transfer efficiency, these findings suggest that adenoviruses can be used to deliver therapeutically active genes into human arteries.
Laitinen
M
M
A.I. Virtanen Institute, Department of Medicine, University of Kuopio, Finland.
Mäkinen
K
K
Manninen
H
H
Matsi
P
P
Kossila
M
M
Agrawal
R S
RS
Pakkanen
T
T
Luoma
J S
JS
Viita
H
H
Hartikainen
J
J
Alhava
E
E
Laakso
M
M
Ylä-Herttuala
S
S
D000256:Adenoviridae / Q000201:enzymology / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D002404:Catheterization; D002908:Chronic Disease; D005240:Feasibility Studies; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D007511:Ischemia / Q000628:therapy*; D007866:Leg / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D014764:Viral Proteins; D001616:beta-Galactosidase