A Novel Pancreatropic Coxsackievirus Vector Expressing Glucagon-Like Peptide 1 Reduces Hyperglycemia in Streptozotocin-Treated Mice

Abstract

A coxsackievirus vector, vCVB(dm) (v stands for vector, CVB stands for group B coxsackievirus, and dm stands for double mutant), has been produced from a unique strain of coxsackievirus B3 (CVB3) containing 2 mutations that confer the property of highly selective pancreatropism. This vector has been tested as a delivery vehicle for glucagon-like peptide 1 (GLP-1), a peptide that enhances pancreatic regeneration following tissue damage. vCVB(dm) is a live vector comprising the entire plus-strand RNA genome with a multiple cloning site (MCS) inserted between the P1 and P2 gene regions. The MCS is flanked by sequences encoding the cleavage site for viral protease 2Apro that processes the polyprotein to release the incorporated gene. Our studies show that this vector selectively delivers GLP-1 to the pancreas where it is expressed in foci scattered throughout the acinar tissue for 4 or 5 days. Moreover, expression is associated with new beta cell clusters in juxtaposition to vector-infected cells. Inoculation of streptozotocin (STZ)-treated mice with vCVB(dm)GLP-1 was found to suppress development of hyperglycemia and increase insulin production relative to mice treated with STZ alone or with empty vector. This vector has the advantage of exclusively targeting pancreas and has potential use for short-term gene delivery to this tissue. The lack of viral integration provides a significant safety feature, making this vector a possible option for use as a therapeutic tool for pancreas-related diseases, including type 1 and 2 diabetes, pancreatitis, and pancreatic cancer.

The relationship between the expression of PLIN3 and PLIN5 protein flowing endurance training in streptozotocin rats

“…Our findings further indicated that insulin resistance, along with low-intensity and highintensity endurance activities in diabetic rats, decreased significantly. Similarly, the destruction of pancreas by STZ leads to a sharp decrease in insulin levels, and owing to hyperglycemia (20), the loss of muscle mass is observed in the models of a severe decrease in insulin (30). Frequent impulses during training are also shown to coordinate the enzymes associated with the metabolism of IMTG (31), because of which endurance-trained athletes have high amounts of IMTG but are insulin sensitive.…”

GLP-1-mediated gene therapy approaches for diabetes treatment

“…Injection of GLP-1-expressing vCVB(dm) (vCVB(dm)GLP-1) reduced STZ-induced hyperglycaemia in diabetic Balb/c mice through enhancement of pancreatic insulin content and stimulation of beta-cell neogenesis (Ref. 80). However, vCVB(dm)GLP-1 could provide only transient gene expression lasting 4–7 days due to low transduction rate, inflammatory response and inability to integrate into the host genome.…”

Antibody-mediated oral delivery of therapeutic DNA for type 2 diabetes mellitus

“…Therapeutic gene delivery systems with various gene carriers including nonviral vectors are potential solutions to the limitations of current diabetic treatments. Nonviral gene delivery is achieved by either nano-size gene complexation or adsorption of the gene to nanoparticles through an interaction between negatively charged DNA and nonviral cationic carriers such as polymers, lipids and inorganic materials [ 8 ]. Recent advances and consideration of the prospects for their application provide better methods of diabetic treatment, primarily for the prevention and cure of T2DM.…”

“…Recent advances and consideration of the prospects for their application provide better methods of diabetic treatment, primarily for the prevention and cure of T2DM. However, direct intravenous injection of these systems limited further application of gene delivery regarding serum stability, immunogenicity, low transfection efficiency and high costs, encouraging researchers to focus on alternative systems [ 8 , 14 – 20 ].…”