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Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia.
Gene Ther. 2006 Sep; 13(17):1281-9.GT

Abstract

The deficiency of glucose-6-phosphatase (G6Pase) underlies life-threatening hypoglycemia and growth retardation in glycogen storage disease type Ia (GSD-Ia). An adeno-associated virus (AAV) vector encoding G6Pase was pseudotyped as AAV8 and administered to 2-week-old GSD-Ia mice (n = 9). Median survival was prolonged to 7 months following vector administration, in contrast to untreated GSD-Ia mice that survived for only 2 weeks. Although GSD-Ia mice were initially growth-retarded, treated mice increased fourfold in weight to normal size. Blood glucose was partially corrected by 2 weeks following treatment, whereas blood cholesterol normalized. Glucose-6-phosphatase activity was partially corrected to 25% of the normal level at 7 months of age in treated mice, and blood glucose during fasting remained lower in treated, affected mice than in normal mice. Glycogen storage was partially corrected in the liver by 2 weeks following treatment, but reaccumulated to pre-treatment levels by 7 months old (m.o.). Vector genome DNA decreased between 3 days and 3 weeks in the liver following vector administration, mainly through the loss of single-stranded genomes; however, double-stranded vector genomes were more stable. Although CD8+ lymphocytic infiltrates were present in the liver, partial biochemical correction was sustained at 7 m.o. The development of efficacious AAV vector-mediated gene therapy could significantly reduce the impact of long-term complications in GSD-Ia, including hypoglycemia, hyperlipidemia and growth failure.

Authors+Show Affiliations

Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA. dwight.koeberl@duke.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16672983

Citation

Koeberl, D D., et al. "Early, Sustained Efficacy of Adeno-associated Virus Vector-mediated Gene Therapy in Glycogen Storage Disease Type Ia." Gene Therapy, vol. 13, no. 17, 2006, pp. 1281-9.
Koeberl DD, Sun BD, Damodaran TV, et al. Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia. Gene Ther. 2006;13(17):1281-9.
Koeberl, D. D., Sun, B. D., Damodaran, T. V., Brown, T., Millington, D. S., Benjamin, D. K., Bird, A., Schneider, A., Hillman, S., Jackson, M., Beaty, R. M., & Chen, Y. T. (2006). Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia. Gene Therapy, 13(17), 1281-9.
Koeberl DD, et al. Early, Sustained Efficacy of Adeno-associated Virus Vector-mediated Gene Therapy in Glycogen Storage Disease Type Ia. Gene Ther. 2006;13(17):1281-9. PubMed PMID: 16672983.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia. AU - Koeberl,D D, AU - Sun,B D, AU - Damodaran,T V, AU - Brown,T, AU - Millington,D S, AU - Benjamin,D K,Jr AU - Bird,A, AU - Schneider,A, AU - Hillman,S, AU - Jackson,M, AU - Beaty,R M, AU - Chen,Y T, Y1 - 2006/05/04/ PY - 2006/5/5/pubmed PY - 2007/1/19/medline PY - 2006/5/5/entrez SP - 1281 EP - 9 JF - Gene therapy JO - Gene Ther. VL - 13 IS - 17 N2 - The deficiency of glucose-6-phosphatase (G6Pase) underlies life-threatening hypoglycemia and growth retardation in glycogen storage disease type Ia (GSD-Ia). An adeno-associated virus (AAV) vector encoding G6Pase was pseudotyped as AAV8 and administered to 2-week-old GSD-Ia mice (n = 9). Median survival was prolonged to 7 months following vector administration, in contrast to untreated GSD-Ia mice that survived for only 2 weeks. Although GSD-Ia mice were initially growth-retarded, treated mice increased fourfold in weight to normal size. Blood glucose was partially corrected by 2 weeks following treatment, whereas blood cholesterol normalized. Glucose-6-phosphatase activity was partially corrected to 25% of the normal level at 7 months of age in treated mice, and blood glucose during fasting remained lower in treated, affected mice than in normal mice. Glycogen storage was partially corrected in the liver by 2 weeks following treatment, but reaccumulated to pre-treatment levels by 7 months old (m.o.). Vector genome DNA decreased between 3 days and 3 weeks in the liver following vector administration, mainly through the loss of single-stranded genomes; however, double-stranded vector genomes were more stable. Although CD8+ lymphocytic infiltrates were present in the liver, partial biochemical correction was sustained at 7 m.o. The development of efficacious AAV vector-mediated gene therapy could significantly reduce the impact of long-term complications in GSD-Ia, including hypoglycemia, hyperlipidemia and growth failure. SN - 0969-7128 UR - https://www.unboundmedicine.com/medline/citation/16672983/Early_sustained_efficacy_of_adeno_associated_virus_vector_mediated_gene_therapy_in_glycogen_storage_disease_type_Ia_ L2 - http://dx.doi.org/10.1038/sj.gt.3302774 DB - PRIME DP - Unbound Medicine ER -