Modulation of Starling Forces and Muscle Fiber Maturity Permits Adenovirus-Mediated Gene Transfer to Adult Dystrophic (mdx) Mice by the Intravascular Route
| Autor: | Josephine Nalbantoglu, Rénald Gilbert, Won Kyung Cho, George Karpati, Basil J. Petrof, Paul C. Holland, Bernard Massie, Satoru Ebihara |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Coxsackie and Adenovirus Receptor-Like Membrane Protein
medicine.medical_specialty animal diseases viruses Duchenne muscular dystrophy Genetic enhancement Genetic Vectors Muscle Fibers Skeletal Hydrostatic pressure Population Biology medicine.disease_cause Muscular Dystrophies Adenoviridae Dystrophin Rats Sprague-Dawley Mice Internal medicine Genetics medicine Animals Myocyte Muscle Skeletal education Molecular Biology education.field_of_study Genetic transfer Gene Transfer Techniques Skeletal muscle medicine.disease Mice Mutant Strains Biomechanical Phenomena Rats Cell biology Endocrinology medicine.anatomical_structure Gene Expression Regulation Injections Intra-Arterial Receptors Virus Molecular Medicine |
| Zdroj: | Human Gene Therapy. 11:701-714 |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/10430340050015608 |
| Popis: | Duchenne muscular dystrophy (DMD) and other inherited myopathies lead to progressive destruction of most skeletal muscles in the body, including those responsible for maintaining respiration. DMD is a fatal disorder caused by defects in the dystrophin gene. Recombinant adenovirus vectors (AdV) are considered a promising means for therapeutic delivery of a functional dystrophin gene to DMD muscles. If AdV-mediated dystrophin gene replacement in DMD is to be successful, development of a systemic delivery method for targeting the large number of diseased muscles will be required. In this study we investigated two major factors preventing efficient AdV-mediated gene transfer to skeletal muscles of adult animals after intravascular AdV administration: (1) an inability of AdV particles to breach the endothelial barrier and enter into contact with myofibers, and (2) a relatively nonpermissive myofiber population for AdV infection due at least in part to insufficient levels of the coxsackie/adenovirus attachment receptor (CAR). On the basis of established principles governing the transendothelial flux of macromolecules, we further hypothesized that an alteration in Starling forces (increased hydrostatic and decreased osmotic pressures) within the intravascular compartment would facilitate AdV transendothelial flux via convective transport. In addition, experimental muscle regeneration was employed to increase the prevalence of immature myofibers in which CAR expression is upregulated. Here we report that by employing the above-described strategy, high-level heterologous reporter gene expression was achievable in hindlimb muscles of normal rats as well as dystrophic (mdx) mice (genetic homolog of DMD) after a single intraarterial injection of AdV. Microsphere studies confirmed enhanced transport into muscle of fluorescent tracer particles in the size range of AdV, and there was a high concordance between CAR upregulation and myofiber transduction after intraarterial AdV delivery. Furthermore, in mdx mice examined 10 days after intraarterial AdV delivery, the aforementioned procedures had no adverse effects on the force-generating capacity of targeted muscles. These findings have implications for eventual AdV-mediated gene therapy of generalized skeletal muscle diseases such as DMD using a systemic intraarterial delivery approach. |
| Databáze: | OpenAIRE |
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