In Vivo Zinc Finger Nuclease-mediated Targeted Integration of a Glucose-6-phosphatase Transgene Promotes Survival in Mice With Glycogen Storage Disease Type IA.

Journal Article (Journal Article)

Glycogen storage disease type Ia (GSD Ia) is caused by glucose-6-phosphatase (G6Pase) deficiency in association with severe, life-threatening hypoglycemia that necessitates lifelong dietary therapy. Here we show that use of a zinc-finger nuclease (ZFN) targeted to the ROSA26 safe harbor locus and a ROSA26-targeting vector containing a G6PC donor transgene, both delivered with adeno-associated virus (AAV) vectors, markedly improved survival of G6Pase knockout (G6Pase-KO) mice compared with mice receiving the donor vector alone (P < 0.04). Furthermore, transgene integration has been confirmed by sequencing in the majority of the mice treated with both vectors. Targeted alleles were 4.6-fold more common in livers of mice with GSD Ia, as compared with normal littermates, at 8 months following vector administration (P < 0.02). This suggests a selective advantage for vector-transduced hepatocytes following ZFN-mediated integration of the G6Pase vector. A short-term experiment also showed that 3-month-old mice receiving the ZFN had significantly-improved biochemical correction, in comparison with mice that received the donor vector alone. These data suggest that the use of ZFNs to drive integration of G6Pase at a safe harbor locus might improve vector persistence and efficacy, and lower mortality in GSD Ia.

Full Text

Duke Authors

Cited Authors

  • Landau, DJ; Brooks, ED; Perez-Pinera, P; Amarasekara, H; Mefferd, A; Li, S; Bird, A; Gersbach, CA; Koeberl, DD

Published Date

  • April 2016

Published In

Volume / Issue

  • 24 / 4

Start / End Page

  • 697 - 706

PubMed ID

  • 26865405

Pubmed Central ID

  • PMC4886939

Electronic International Standard Serial Number (EISSN)

  • 1525-0024

Digital Object Identifier (DOI)

  • 10.1038/mt.2016.35


  • eng

Conference Location

  • United States