Treatment of Diabetes and Long-Term Survival After Insulin and Glucokinase Gene Therapy
- David Callejas1,2,5,
- Christopher J. Mann1,2,5,
- Eduard Ayuso1,2,5,
- Ricardo Lage1,2,5,
- Iris Grifoll1,2,5,
- Carles Roca1,2,5,
- Anna Andaluz3,
- Rafael Ruiz-de Gopegui3,
- Joel Montané1,2,
- Sergio Muñoz1,2,5,
- Tura Ferre1,2,5,
- Virginia Haurigot1,2,5,
- Shangzhen Zhou6,
- Jesús Ruberte1,4,5,
- Federico Mingozzi6,
- Katherine A. High6,7,
- Felix Garcia3 and
- Fatima Bosch1,2,5⇑
- 1Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma Barcelona, Bellaterra, Spain
- 2Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma Barcelona, Bellaterra, Spain
- 3Department of Animal Medicine and Surgery, School of Veterinary Medicine, Universitat Autònoma Barcelona, Bellaterra, Spain
- 4Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma Barcelona, Bellaterra, Spain
- 5CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
- 6Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
- 7Howard Hughes Medical Institute, Philadelphia, Pennsylvania
- Corresponding author: Fatima Bosch,
D.C. and C.J.M. contributed equally to this study.
Diabetes is associated with severe secondary complications, largely caused by poor glycemic control. Treatment with exogenous insulin fails to prevent these complications completely, leading to significant morbidity and mortality. We previously demonstrated that it is possible to generate a “glucose sensor” in skeletal muscle through coexpression of glucokinase and insulin, increasing glucose uptake and correcting hyperglycemia in diabetic mice. Here, we demonstrate long-term efficacy of this approach in a large animal model of diabetes. A one-time intramuscular administration of adeno-associated viral vectors of serotype 1 encoding for glucokinase and insulin in diabetic dogs resulted in normalization of fasting glycemia, accelerated disposal of glucose after oral challenge, and no episodes of hypoglycemia during exercise for >4 years after gene transfer. This was associated with recovery of body weight, reduced glycosylated plasma proteins levels, and long-term survival without secondary complications. Conversely, exogenous insulin or gene transfer for insulin or glucokinase alone failed to achieve complete correction of diabetes, indicating that the synergistic action of insulin and glucokinase is needed for full therapeutic effect. This study provides the first proof-of-concept in a large animal model for a gene transfer approach to treat diabetes.
This article contains Supplementary Data and videos online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1113/-/DC1.
See accompanying commentary, p. 1396.
- Received August 17, 2012.
- Accepted January 28, 2013.
- © 2013 by the American Diabetes Association.
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