Gene therapy promises to be a cure for the muscular dystrophies, such as Duchenne muscular dystrophy. Studies by my laboratory and others indicate that the transfer of the normal human dystrophin gene into dystrophic muscle (in the mouse model) prevents the death of the myofiber. The critical problem now is how to deliver the normal dystrophin gene to enough of the muscle cells and have it stably expressed in order to effect a cure. We have spectacular preliminary results that show that plasmid DNA can be delivered via a blood vessel into more than 10 percent of the muscle cells throughout the leg of a rat. This percentage of transfected muscle cells approaches the critical minimum percentage necessary to be curative in children with Duchenne muscular dystrophy. With this approach, multiple administrations should be possible, ensuring that a sufficient number of cells would be converted to dystrophin-positivity. Our studies also indicate that this approach should lead to stable expression of the gene. We have shown that the intravascular injection of naked plasmid DNA (pDNA) into the femoral artery of rats leads to very high foreign gene expression in skeletal muscle throughout the leg and without damaging the muscle. Previous experience with naked DNA and adenoviral vectors showed that the gene transfer efficiency decreased substantially when going from the young mouse, to adult mouse and then adult rat. The fact that we can achieve very efficient expression in an adult rat is quite encouraging. The objective of this proposal is to extend this approach to larger animals, non-human primates and the dog and its associated Duchenne model. If successful in primates and dogs, a human clinical trial in patients with Duchenne muscular dystrophy could begin in the near future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039915-05
Application #
6793313
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Porter, John D
Project Start
2000-09-30
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
5
Fiscal Year
2004
Total Cost
$324,000
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Vigen, Karl K; Hegge, Julia O; Zhang, Guofeng et al. (2007) Magnetic resonance imaging-monitored plasmid DNA delivery in primate limb muscle. Hum Gene Ther 18:257-68
Zhang, Goufeng; Ludtke, James J; Thioudellet, Christine et al. (2004) Intraarterial delivery of naked plasmid DNA expressing full-length mouse dystrophin in the mdx mouse model of duchenne muscular dystrophy. Hum Gene Ther 15:770-82