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.