Journal
GENE THERAPY
Volume 10, Issue 18, Pages 1551-1558Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3302046
Keywords
adeno-associated virus; diabetes; targeting
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Funding
- NHLBI NIH HHS [HL59412, HL51811] Funding Source: Medline
- NIDDK NIH HHS [DK58327] Funding Source: Medline
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Human pancreatic islet cells and hepatocytes represent the two most likely target cells for genetic therapy of type I diabetes. However, limits to the efficiency of rAAV serotype 2 (rAAV2)-mediated gene transfer have been reported for both of these cell targets. Here we report that nonserotype 2 AAV capsids can mediate more efficient transduction of islet cells, with AAV1 being the most efficient serotype in murine islets, suggesting that receptor abundance could be limiting. In order to test this, we generated rAAV particles that display a ligand (ApoE) that targets the low-density lipoprotein receptor, which is present on both of these cell types. The rAAV/ApoE viruses greatly enhanced the efficiency of transduction of both islet cells ex vivo and murine hepatocytes in vivo when compared to native rAAV2 serotype (220- and four-fold, respectively). The use of receptor-targeted rAAV particles may circumvent the lower abundance of receptors on certain nonpermissive cell types.
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