title: Successful β cells islet regeneration in streptozotocin-induced diabetic baboons using ultrasound-targeted microbubble gene therapy with cyclinD2/CDK4/GLP1.
abstract: Both major forms of diabetes mellitus (DM) involve β-cell destruction and dysfunction. New treatment strategies have focused on replenishing the deficiency of β-cell mass common to both major forms of diabetes by islet transplantation or β-cell regeneration. The pancreas, not the liver, is the ideal organ for islet regeneration, because it is the natural milieu for islets. Since islet mass is known to increase during obesity and pregnancy, the concept of stimulating pancreatic islet regeneration in vivo is both rational and physiologic. This paper proposes a novel approach in which non-viral gene therapy is targeted to pancreatic islets using ultrasound targeted microbubble destruction (UTMD) in a non-human primate model (NHP), the baboon. Treated baboons received a gene cocktail comprised of cyclinD2, CDK, and GLP1, which in rats results in robust and durable islet regeneration with normalization of blood glucose, insulin, and C-peptide levels. We were able to generate important preliminary data indicating that gene therapy by UTMD can achieve in vivo normalization of the intravenous (IV) glucose tolerance test (IVGTT) curves in STZ hyperglycemic-induced conscious tethered baboons. Immunohistochemistry clearly demonstrated evidence of islet regeneration and restoration of β-cell mass.
authors.affiliation: Baylor Research Institute; Dallas, TX USA.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Texas Biomedical Research Institute; San Antonio, TX USA; Southwest National Primate Research Center; San Antonio, TX USA.
authors.forename: Raul A
authors.initials: RA
authors.lastname: Bastarrachea
authors.affiliation: Baylor Research Institute; Dallas, TX USA; Department of Internal Medicine; Division of Cardiology; Baylor Heart and Vascular Institute; Baylor University Medical Center; Dallas, TX USA.
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Roberts
authors.affiliation: Texas Biomedical Research Institute; San Antonio, TX USA.
authors.forename: V Saroja
authors.initials: VS
authors.lastname: Voruganti
authors.affiliation: Texas Biomedical Research Institute; San Antonio, TX USA; Southwest National Primate Research Center; San Antonio, TX USA.
authors.forename: Patrice A
authors.initials: PA
authors.lastname: Frost
authors.affiliation: Texas Biomedical Research Institute; San Antonio, TX USA; University of Nuevo Leon School of Nutrition and Public Health; Monterrey, Mexico.
authors.forename: Edna J
authors.initials: EJ
authors.lastname: Nava-Gonzalez
authors.affiliation: Texas Biomedical Research Institute; San Antonio, TX USA; Hospital Infantil de Tamaulipas; Ciudad Victoria, Mexico.
authors.forename: Hector E
authors.initials: HE
authors.lastname: Arriaga-Cazares
authors.affiliation: Baylor Research Institute; Dallas, TX USA.
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Ultrasonography; The 2nd Affiliated Hospital of Zhejiang University College of Medicine; Hangzhou, Zhejiang Province, PR China.
authors.forename: Pintong
authors.initials: P
authors.lastname: Huang
authors.affiliation: Diabetes Division; Department of Medicine; The University of Texas Health Science Center at San Antonio; San Antonio, TX USA.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
authors.affiliation: Texas Biomedical Research Institute; San Antonio, TX USA; Southwest National Primate Research Center; San Antonio, TX USA.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Comuzzie
authors.affiliation: Department of Internal Medicine; Division of Cardiology; Baylor Heart and Vascular Institute; Baylor University Medical Center; Dallas, TX USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Grayburn
mesh_terms: D000818:Animals; D056742:Cyclin D2 / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015316:Genetic Therapy; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000503:physiopathology; D010215:Papio; D010865:Pilot Projects; D012038:Regeneration; D013311:Streptozocin; D000069453:Ultrasonic Waves
chemical_list: D056742:Cyclin D2; D000067757:Glucagon-Like Peptide-1 Receptor; D013311:Streptozocin; D051358:Cyclin-Dependent Kinase 4
keywords: CDK4; CyclinD2; GLP-1; baboons; cell cycle regulation; diabetes; differentiation; gene therapy; insulin gene promoter; islets regeneration; nonhuman primates; proliferation