Long-term, antidiabetogenic effects of GLP-1 gene therapy using a double-stranded, adeno-associated viral vector.
Diabetes is characterized by insulin resistance and a reduction in insulin secretion, leading to progressive β-cell failure and loss of β-cell mass. Its central therapeutic issues are how to restore glucose responsiveness of β-cells to normal and counteract defects in insulin secretion. Native glucagon-like peptide-1 (GLP-1), which makes β-cells competent and diabetic β-cells specifically more sensitive to glucose, has a major drawback of rapid inactivation. In this study, we describe the construction and analysis of a GLP-1 plasmid and double-stranded, adeno-associated viral (dsAAV) expression vector to overcome both the rapid degradation of native GLP-1 and limitations of gene therapy using standard single-stranded AAV. Our study results demonstrate that fasting blood glucose levels of db/db obese mice decreased significantly up to 4 months after a single injection of dsAAV GLP-1, and both insulin and circulating GLP-1 levels increased in dsAAV GLP-1-infected mice. These results demonstrate that dsAAV GLP-1 has long-term, efficient transgene expression with minimal toxicity and cellular immune responses. This study suggests that GLP-1 produced by dsAAV may be an alternative to the continuous infusions required for GLP-1 peptide therapy or daily injections of GLP-1.
Choi
S H
SH
Department of Endocrinology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, Korea.
Lee
H C
HC
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004247:DNA; D000229:Dependovirus / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D052216:Glucagon-Like Peptide 1 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese
D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D004247:DNA