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| In vivo muscle gene transfer of full-length dystrophin with an adenoviral vector that lacks all viral genes |
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| Author(s): Clemens PR, Kochanek S, Sunada Y, Chan S, Chen HH, Campbell KP, Caskey CT |
| Source: GENE THERAPY Volume: 3 Issue: 11 Pages: 965-972 Published: NOV 1996 |
| Times Cited: 144 References: 30 |
| Abstract: Duchenne muscular dystrophy (DMD) is an important target for gene transfer because of the disease's high frequency and devastating course. To date, adenoviral vector-mediated gene transfer for DMD has been unavailable because (1) adenoviral vectors were unable to accommodate the full-length dystrophin cDNA (14 kb); and (2) adenoviral vectors induced inflammatory reactions in the gene transfer recipient. We addressed both problems with a novel adenoviral vector that contains no viral genes and encodes 28.2 kb of foreign DNA including both the full-length dystrophin cDNA with the muscle creatine kinase promoter for transcriptional control and a lacZ marker gene. This report presents the in vivo expression of dystrophin and beta-galactosidase from this vector in skeletal muscle of the mdx mouse, a mutant mouse that lacks dystrophin. Somatic delivery of the vector by intramuscular injection in 6-day-old mice resulted in the expression of full-length, recombinant dystrophin at the muscle membrane. Dystrophin-associated proteins were restored in muscle fibers expressing recombinant dystrophin. Mdx muscle injected with our vector showed a decrease in the proportion of fibers with nuclei located centrally; centrally placed nuclei in muscle fibers are characteristic of cycles of degeneration and regeneration suffered by dystrophin-deficient muscle tissue. These results are strong evidence that adenoviral vector-mediated full-length dystrophin delivery provides substantial somatic function. |
| Document Type: Article |
| Language: English |
| Reprint Address: Clemens, PR (reprint author), UNIV PITTSBURGH, DEPT NEUROL, BIOMED SCI TOWER S-515, PITTSBURGH, PA 15213 USA |
Addresses:
1. BAYLOR COLL MED, DEPT MOL & HUMAN GENET, HOUSTON, TX 77030 USA
2. UNIV IOWA, DEPT PHYSIOL & BIOPHYS, COLL MED, IOWA CITY, IA 52242 USA
3. UNIV IOWA, COLL MED, HOWARD HUGHES MED INST, IOWA CITY, IA 52242 USA
4. MERCK RES LABS, W POINT, PA USA |
| Publisher: STOCKTON PRESS, HOUNDMILLS, BASINGSTOKE, HAMPSHIRE, ENGLAND RG21 6XS |
| Subject Category: Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental |
| IDS Number: VR643 |
| ISSN: 0969-7128 |
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