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386 ADENO-ASSOCIATED VIRAL VECTORS FOR IN UTERO GENE THERAPY OF INHERITED METABOLIC DISEASE.
  1. S. Patel1,
  2. C. -L. Gau2,
  3. S. Cederbaum2,
  4. R. W. Busuttil1,
  5. G. S. Lipshutz1
  1. 1Department of Surgery
  2. 2Department of Medical Genetics, University of California, Los Angeles

Abstract

Introduction Recombinant adeno-associated viral vectors (rAAV), derived from the nonpathogenic human parvovirus family, provide a promising means of affording long-term gene expression without toxicity. The recent discovery of novel AAV serotypes that differ in their ability to transduce different cell types has provided investigators with increasing control over directing gene expression to sites of interest. The purpose of the present study was to compare AAV2 and AAV1 as potential agents for in utero gene therapy.

Methods We used whole-body and individual tissue bioluminescent imaging to compare the expression profiles of AAV1 and AAV2 gene transfer vectors. 1011 viral genomes of either AAV2 or AAV1 were injected intraperitoneally at 15 days of gestation in fetal mice. Vectors contained the luciferase cDNA under the control of either the CMV or the EF1α promoter.

Results Using bioluminescent imaging, we were able to detect levels of transgene activity by 6 weeks after birth following in utero administration of rAAV. Confirmatory studies with PCR demonstrated the presence of viral DNA in all tissues examined in the AAV1 model.

Conclusion These results support the increasing use of rAAV in gene therapy. In addition, they support the need for examining other rAAV serotypes as a novel means of achieving early high-level expression of therapeutic genes by an in utero approach as a method to prevent the onset of phenotypic disease.

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