Biodistribution and safety studies of hDel-1 plasmid-based gene therapy in mouse and rabbit models.
A plasmid encoding the human developmentally regulated endothelial locus-1 (hDel-1) protein formulated with poloxamer 188 is a potential gene therapy for peripheral arterial disease in man. As a prelude to clinical trials, the biodistribution and safety of this therapy were evaluated after intramuscular and intravenous administration in mice and rabbits. In mice, plasmid DNA persisted at the intramuscular injection site for at least 28 days, but was barely detectable in distal tissues by 24 h and essentially cleared by 28 days. By 24 h after intravenous administration, plasmid DNA was readily detected in blood, muscle, and lungs but sporadically and at low levels in other tissues. At 28 days, plasmid DNA was readily detectable only at the intravenous injection site (tail) after low- and high-dose administration, and sporadically in blood and muscle after high-dose administration. In rabbits, the highest intramuscular (4.2 mg kg(-1)) or intravenous (3.7 mg kg(-1)) dose caused no deaths; no treatment-related clinical signs; no changes in body weight, clinical pathology parameters, ophthalmology, ECG, or histopathology; and no detectable increase in antinuclear antibodies by 28 days. The results supported testing of hDel-1 plasmid-based gene therapy in phase I clinical trials.
Valentis, Inc., Burlingame, CA, USA. aquezada@stillmeadow.com
Abraham
A
Quezada
Jeff
J
Larson
Martha
M
French
Rafael
R
Ponce
Jerry
J
Perrard
Ross
R
Durland
Michael
M
Coleman
D000818:Animals; D001682:Biological Availability; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000493:pharmacokinetics*; D015815:Cell Adhesion Molecules; D004247:DNA / Q000235:genetics; D004337:Drug Carriers; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects; D010957:Plasmids / Q000235:genetics*; D020442:Poloxamer / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D011817:Rabbits; D013997:Time Factors
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D004337:Drug Carriers; C110183:EDIL3 protein, human; C491706:Edil3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D020442:Poloxamer; D004247:DNA