Incorporation of calcium phosphate enhances recombinant adeno‐associated virus‐mediated gene therapy in diabetic mice

Abstract

Administration of rAAV harboring the human insulin gene into livers of the STZ-diabetic mice improved blood glucose levels, maintained body weight of the diabetic animals, and resulted in human insulin secretion. Complexation of rAAV with calcium phosphate significantly potentiated the efficiency of rAAV-mediated diabetic gene therapy.

Long‐term glycemic control with hepatic insulin gene therapy in streptozotocin‐diabetic mice

“…Yang et al . also used helper adenovirus to produce their AAV vectors, again suggesting additional effects to AAV2 transduction alone. Park et al .…”

Long-Term Efficacy and Safety of Insulin and Glucokinase Gene Therapy for Diabetes: 8-Year Follow-Up in Dogs

“…Some of the previous gene therapy approaches developed to counteract diabetic hyperglycemia relied on the glucose-regulated expression of Ins in surrogate non-β cells to respond to the changes in blood glucose 24, 25, 26, 27, 28, 29, 30. Both naturally occurring and engineered hybrid promoters have been used to achieve glucose-responsive expression of Ins following in vivo delivery of gene transfer vectors 24, 25, 26, 27, 28, 29, 30.…”

“…Both naturally occurring and engineered hybrid promoters have been used to achieve glucose-responsive expression of Ins following in vivo delivery of gene transfer vectors 24, 25, 26, 27, 28, 29, 30. None of these systems, however, has managed to mimic the quick response to glucose of the Ins promoter, 31 and the slow transcriptional activation of these promoters may result in an inadequate Ins secretory response, with postprandial episodes of hyperglycemia followed by hypoglycemia several hours later.…”

Glucose- and Metabolically Regulated Hepatic Insulin Gene Therapy for Diabetes

“…In an effort to mimic the physiological conditions of insulin secretion, attempts have been made by various means to control insulin secretion in response to blood glucose levels. Strategies used for transcriptional control of insulin secretion include the utilization of glucoseresponsive elements (GREs) of the rat L-pyruvate kinase (L-PK) gene, inserted into the insulin-sensitive element of rat insulin-like growth factor binding protein-1 (IGFBP-1) promoter (1,2); employment of genetically engineered cells to over-express key regulatory genes such as glucokinase (GK) in skeletal muscle (3,4); the use of phosphoenolpyruvate carboxykinase (PEPCK) promoter (5)(6)(7); and expression of the GLUT2 glucose transporter (8), etc. A combination of constructs with modified insulin gene and suitable gene delivery vectors has demonstrated partial success in the generation of glucose-modulated insulin secretion.…”