title: Gene transfer to muscle from the isolated regional circulation.
abstract: Vector transport across the endothelium has long been regarded as one of the central "bottlenecks" in gene therapy research, especially as it pertains to the muscular dystrophies where the target tissue approaches half of the total body mass. Clinical studies of gene therapy for hemophilia B revealed the limitations of the intramuscular route, compelling an aggressive approach to the study of scale-independent circulatory means of vector delivery. The apparent permeability of the microvasculature in small animals suggests that gravitational and/or inertial effects on the circulation require progressive restriction of fluid and solute flow across the capillary wall with increasing body size. To overcome this physiological restriction, we initially used a combined surgical and pharmacological approach to temporarily alter permeability within the isolated pelvic limb. Although this was successful, new information about the cell and molecular biology of histamine-induced changes in microvascular permeability suggested an alternative approach, which substituted pressure-induced transvenular extravasation. Here we outline the details of our surgical approaches in the rat. We also discuss the modifications that are appropriate for the dog.
authors.affiliation: Department of Surgery, Division of Gastrointestinal Surgery, University of Pennsylvania School of Medicine, BRB II/III Building, 421 Currie Boulevard, Philadelphia, PA, USA.
authors.forename: Mihail
authors.initials: M
authors.lastname: Petrov
authors.forename: Alock
authors.initials: A
authors.lastname: Malik
authors.forename: Andrew
authors.initials: A
authors.lastname: Mead
authors.forename: Charles R
authors.initials: CR
authors.lastname: Bridges
authors.forename: Hansell H
authors.initials: HH
authors.lastname: Stedman
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002196:Capillaries / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects; D000229:Dependovirus; D004195:Disease Models, Animal; D004285:Dogs; D004727:Endothelium / Q000098:blood supply*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006467:Hemophilia A / Q000628:therapy; D006614:Hindlimb; D006632:Histamine / Q000494:pharmacology; D009132:Muscles / Q000098:blood supply*; D009136:Muscular Dystrophies / Q000628:therapy; D010208:Papaverine / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D006632:Histamine; D010208:Papaverine