Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 12, Pages 6716-6721Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.97.12.6716
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Funding
- NHLBI NIH HHS [R01 HL58340, R01 HL058340] Funding Source: Medline
- NIDDK NIH HHS [P30 DK54759, P30 DK054759] Funding Source: Medline
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Adeno-associated viral (AAV) vectors have demonstrated considerable promise for gene therapy of inherited diseases. However, with a packaging size of <5 kb. applications have been limited to relatively small disease genes. Based on the finding that AAV genomes undergo intermolecular circular concatamerization after transduction in muscle, we have developed a paradigm to increase the size of delivered transgenes with this vector through trans-splicing between two independent vectors coadministered to the same tissue. When two vectors encoding either the 5' or 3' portions of the erythropoietin genomic locus were used, functional erythropoietin protein was expressed in muscle subsequent to the formation of intermolecular circular concatamers in a head-to-tail orientation through transsplicing between these two independent vector genomes, These findings will allow for the application of AAV technologies to a wider variety of diseases for which therapeutic transgenes exceed the packaging limitation of present AAV vectors.
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