Sustained Exendin-4 Secretion through Gene Therapy Targeting Salivary Glands in Two Different Rodent Models of Obesity/Type 2 Diabetes

Exendin-4 (Ex-4) is a Glucagon-like peptide 1 (GLP-1) receptor agonist approved for the treatment of Type 2 Diabetes (T2DM), which requires daily subcutaneous administration. In T2DM patients, GLP-1 administration is reported to reduce glycaemia and HbA1c in association with a modest, but significant weight loss. The aim of present study was to characterize the site-specific profile and metabolic effects of Ex-4 levels expressed from salivary glands (SG) in vivo, following adeno-associated virus-mediated (AAV) gene therapy in two different animal models of obesity prone to impaired glucose tolerance and T2DM, specifically, Zucker fa/fa rats and high fed diet (HFD) mice. Following percutaneous injection of AAV5 into the salivary glands, biologically active Ex-4 was detected in the blood of both animal models and expression persisted in salivary gland ductal cell until the end of the study. In treated mice, Ex-4 levels averaged 138.9±42.3 pmol/L on week 6 and in treated rats, mean circulating Ex-4 levels were 238.2±72 pmol/L on week 4 and continued to increase through week 8. Expression of Ex-4 resulted in a significant decreased weight gain in both mice and rats, significant improvement in glycemic control and/or insulin sensitivity as well as visceral adipose tissue adipokine profile. In conclusion, these results suggest that sustained site-specific expression of Ex-4 following AAV5-mediated gene therapy is feasible and may be useful in the treatment of obesity as well as trigger improved metabolic profile.

[1]  B. Baum,et al.  Gene delivery in salivary glands: from the bench to the clinic. , 2011, Biochimica et biophysica acta.

[2]  H. Weiler,et al.  Deposition of docosahexaenoic acid (DHA) is limited in forebrain of young obese fa/fa Zucker rats fed a diet high in α-linolenic acid but devoid of DHA. , 2011, The Journal of nutritional biochemistry.

[3]  I. Dicembrini,et al.  From Theory to Clinical Practice in the Use of GLP-1 Receptor Agonists and DPP-4 Inhibitors Therapy , 2011, Experimental diabetes research.

[4]  J. Chiorini,et al.  Glucagon-Like Peptide-1 Gene Therapy , 2011, Experimental diabetes research.

[5]  T. Jin,et al.  A site-specific genomic integration strategy for sustained expression of glucagon-like peptide-1 in mouse muscle for controlling energy homeostasis. , 2010, Biochemical and biophysical research communications.

[6]  Y. Loh,et al.  Systemic delivery of bioactive glucagon-like peptide 1 after adenoviral-mediated gene transfer in the murine salivary gland. , 2010, Endocrinology.

[7]  B. McFarlin,et al.  Weight gain in response to high-fat feeding in CD-1 male mice , 2010, Laboratory animals.

[8]  J. Díaz-Nido.  NLX-P101, an adeno-associated virus gene therapy encoding glutamic acid decarboxylase, for the potential treatment of Parkinson's disease. , 2010, Current opinion in investigational drugs.

[9]  R. Mandel.  CERE-110, an adeno-associated virus-based gene delivery vector expressing human nerve growth factor for the treatment of Alzheimer's disease. , 2010, Current opinion in molecular therapeutics.

[10]  K. Almholt,et al.  Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. , 2010, Endocrinology.

[11]  H. Parker,et al.  Molecular mechanisms underlying nutrient-stimulated incretin secretion , 2010, Expert Reviews in Molecular Medicine.

[12]  Jean Bennett,et al.  Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  A. Astrup,et al.  Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study , 2009, The Lancet.

[14]  Joshua J. Neumiller.  Differential chemistry (structure), mechanism of action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors. , 2009, Journal of the American Pharmacists Association : JAPhA.

[15]  S. Madsbad.  Exenatide and liraglutide: different approaches to develop GLP-1 receptor agonists (incretin mimetics)--preclinical and clinical results. , 2009, Best practice & research. Clinical endocrinology & metabolism.

[16]  N. Marchionni,et al.  Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. , 2009, European journal of endocrinology.

[17]  R. Herzog,et al.  Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. , 2009, Blood.

[18]  S. Samson,et al.  Gene therapy for diabetes: metabolic effects of helper-dependent adenoviral exendin 4 expression in a diet-induced obesity mouse model. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[19]  Kenneth I. Berns,et al.  Gene Therapy Using Adeno-Associated Virus Vectors , 2008, Clinical Microbiology Reviews.

[20]  A. Srivastava,et al.  Adeno‐associated virus‐mediated gene transfer , 2008, Journal of cellular biochemistry.

[21]  F. Gribble.  RD Lawrence Lecture 2008 Targeting GLP-1 release as a potential strategy for the therapy of Type 2 diabetes , 2008, Diabetic medicine : a journal of the British Diabetic Association.

[22]  Nick Tyler,et al.  Effect of gene therapy on visual function in Leber's congenital amaurosis. , 2008, The New England journal of medicine.

[23]  E. Kang,et al.  Adenoviral vector‐mediated glucagon‐like peptide 1 gene therapy improves glucose homeostasis in Zucker diabetic fatty rats , 2008, The journal of gene medicine.

[24]  David V. Schaffer,et al.  Designer Gene Delivery Vectors: Molecular Engineering and Evolution of Adeno-Associated Viral Vectors for Enhanced Gene Transfer , 2007, Pharmaceutical Research.

[25]  E. Hahm,et al.  Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis , 2007, Diabetes.

[26]  L. Davies,et al.  Long-term persistence of gene expression from adeno-associated virus serotype 5 in the mouse airways , 2006, Gene Therapy.

[27]  B. Baum,et al.  Enhanced transduction of mouse salivary glands with AAV5-based vectors , 2006, Gene Therapy.

[28]  S. W. Kim,et al.  Glucagon-like peptide-1 plasmid construction and delivery for the treatment of type 2 diabetes. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[29]  E. Mannucci,et al.  Glucagon-like peptide 1 (GLP-1) and metabolic diseases , 2005, Journal of endocrinological investigation.

[30]  M. Akahane,et al.  Physiological difference between obese (fa/fa) Zucker rats and lean Zucker rats concerning adiponectin. , 2005, Metabolism: clinical and experimental.

[31]  Ioannis Bossis,et al.  Salivary glands as a potential gene transfer target for gene therapeutics of some monogenetic endocrine disorders. , 2005, The Journal of endocrinology.

[32]  Mark E. Schneider,et al.  A novel bovine virus efficiently transduces inner ear neuroepithelial cells. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[33]  K. Stieger,et al.  Long-term doxycycline-regulated transgene expression in the retina of nonhuman primates following subretinal injection of recombinant AAV vectors. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[34]  J. Clancy,et al.  Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebo-controlled trial. , 2004, Chest.

[35]  J. Holst,et al.  Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study , 2002, The Lancet.

[36]  J. Holst,et al.  Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. , 2001, Diabetes.

[37]  E. Mannucci,et al.  Glucagon‐like peptide (GLP)‐1 and leptin concentrations in obese patients with Type 2 diabetes mellitus , 2000, Diabetic medicine : a journal of the British Diabetic Association.

[38]  Y. Marmary,et al.  Systemic action of human growth hormone following adenovirus-mediated gene transfer to rat submandibular glands , 1998, Gene Therapy.

[39]  F. Gage,et al.  Retrovirus‐Mediated Expression of an Artificial β‐Endorphin Precursor in Primary Fibroblasts , 1995, Journal of neurochemistry.

[40]  J. Holst,et al.  Tissue and Plasma Concentrations of Amidated and Glycine-Extended Glucagon-Like Peptide I in Humans , 1994, Diabetes.

[41]  B. Baum,et al.  Human parathyroid hormone is secreted primarily into the bloodstream after rat parotid gland gene transfer. , 2011, Human gene therapy.

[42]  J. Leahy.  Effects of Once-Weekly Dosing of a Long-Acting Release Formulation of Exenatide on Glucose Control and Body Weight in Subjects With Type 2 Diabetes , 2008 .

[43]  Y. Glinka,et al.  Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice , 2007, Gene Therapy.

[44]  H. Holloway,et al.  Insertion of an N-terminal 6-aminohexanoic acid after the 7 amino acid position of glucagon-like peptide-1 produces a long-acting hypoglycemic agent. , 2001, Endocrinology.