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Gene Transfer to Muscle from the Isolated Regional Circulation

  • Mihail Petrov
  • Alock Malik
  • Andrew Mead
  • Charles R. Bridges
  • Hansell H. Stedman
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 709)

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.

Key words

AAV Adenovirus Muscular dystrophy Hemophilia Gene therapy Regional or isolated limb perfusion Histamine Large animal (canine) models 

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Mihail Petrov
    • 1
  • Alock Malik
    • 2
  • Andrew Mead
    • 1
  • Charles R. Bridges
    • 1
  • Hansell H. Stedman
    • 1
  1. 1.Department of Surgery, Division of Gastrointestinal SurgeryUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of SurgeryUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

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