Treatment of Diabetes and Long-term Survival Following Insulin and Glucokinase Gene Therapy

  1. Fatima Bosch
  1. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  2. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  3. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  4. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  5. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  6. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  7. Universitat Autonoma de Barcelona, Department of Animal Medicine and Surgery, School of Veterinary Medicine, Bellaterra, Barcelona, Spain
  8. Universitat Autonoma de Barcelona, Department of Animal Medicine and Surgery, School of Veterinary Medicine, Bellaterra, Barcelona, Spain
  9. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  10. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  11. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  12. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  13. Children's Hospital of Philadelphia, Division of Hematology, Philadelphia, Pennsylvania, United States
  14. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  15. Children's Hospital of Philadelphia, Division of Hematology, Philadelphia, Pennsylvania, United States
  16. Children's Hospital of Philadelphia, Division of Hematology, Philadelphia, Pennsylvania, United States
  17. Universitat Autonoma de Barcelona, Department of Animal Medicine and Surgery, School of Veterinary Medicine, Bellaterra, Barcelona, Spain
  18. Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  1. Corresponding author: Fatima Bosch, fatima.bosch{at}uab.es

Abstract

Diabetes is associated with severe secondary complications, caused largely 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 co-expression of glucokinase (Gck) and insulin (Ins), 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 adenoassociated viral vectors of serotype 1 (AAV1) encoding for Gck and Ins 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 Ins or Gck alone failed to achieve complete correction of diabetes, indicating that the synergistic action of Ins and Gck are 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.

  • Received August 17, 2012.
  • Accepted January 28, 2013.

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