title: Reversal of diabetes through gene therapy of diabetic rats by hepatic insulin expression via lentiviral transduction.
abstract: Due to shortage of donor tissue a cure for type 1 diabetes by pancreas organ or islet transplantation is an option only for very few patients. Gene therapy is an alternative approach to cure the disease. Insulin generation in non-endocrine cells through genetic engineering is a promising therapeutic concept to achieve insulin independence in patients with diabetes. In the present study furin-cleavable human insulin was expressed in the liver of autoimmune-diabetic IDDM rats (LEW.1AR1/Ztm-iddm) and streptozotocin-diabetic rats after portal vein injection of INS-lentivirus. Within 5-7 days after the virus injection of 7 × 10(9) INS-lentiviral particles the blood glucose concentrations were normalized in the treated animals. This glucose lowering effect remained stable for the 1 year observation period. Human C-peptide as a marker for hepatic release of human insulin was in the range of 50-100 pmol/ml serum. Immunofluorescence staining of liver tissue was positive for insulin showing no signs of transdifferentiation into pancreatic β-cells. This study shows that the diabetic state can be efficiently reversed by insulin release from non-endocrine cells through a somatic gene therapy approach.
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Elsner
authors.forename: Taivankhuu
authors.initials: T
authors.lastname: Terbish
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.forename: Ortwin
authors.initials: O
authors.lastname: Naujok
authors.forename: Dirk
authors.initials: D
authors.lastname: Wedekind
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Hedrich
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007275:Injections, Intravenous; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics; D016086:Lentivirus / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D011169:Portal Vein; D051381:Rats; D055647:Rats, Transgenic; D013311:Streptozocin
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D013311:Streptozocin