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Long-Term Efficacy of Gene Therapy for Diabetes Mellitus


A single administration of gene therapy can provide long-term glycemic control without the need for insulin injections for diabetes mellitus.

Researchers in Barcelona, Spain, have published an 8-year follow-up study of dogs treated with gene therapy for experimentally induced type 1 diabetes mellitus. Their results indicate that a single administration of gene therapy can provide long-term glycemic control without the need for insulin injections. The report was published in June in Molecular Therapy—Methods & Clinical Development.

“We believe gene therapy holds great potential for the treatment of diabetes in humans,” wrote the authors. The study provides the longest efficacy data reported to date for gene transfer in a large-animal model of diabetes, they said.

In 2013 the research group published a proof-of-concept study showing that intramuscular gene transfer could correct experimentally induced diabetes mellitus for more than 4 years in beagles. The current article reports the 8-year follow-up results for 2 of the dogs.


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The technique uses an adeno-associated viral vector encoding genes for both insulin and glucokinase. Insulin and glucokinase work together as a “glucose sensor” in skeletal muscle, regulating glucose uptake in response to blood glucose levels, wrote the authors. In diabetic animals receiving this treatment, muscles—not the pancreas—are responsible for glycemic control. The proof-of-concept study showed that treatment with both genes was necessary to control hyperglycemia.

The dogs in the study received an injection of streptozotocin and alloxan at 6 to 12 months of age to induce diabetes mellitus. This research model approximates human type 1 diabetes mellitus but does not exactly replicate it. In type 1 diabetes mellitus, the immune system (rather than an injection of pancreas-targeting agents) destroys the insulin-producing cells of the pancreas.

The investigators administered the therapeutic vectors to the dogs 2 to 4 weeks after inducing diabetes. The vectors were injected into several sites in the muscles of the hind limbs on a single occasion. According to the results published in 2013, this treatment normalized fasting blood glucose levels and prevented hypoglycemia during exercise for over 4 years.

The 8-year follow-up of 2 of the beagles yielded the following results:

  • Fasting blood glucose levels remained normal for 8 years.
  • Weight gain was the same as that expected in healthy dogs.
  • Administration of exogenous insulin was not needed at any time.
  • Circulating blood insulin levels remained at the levels expected in healthy dogs, even though insulin-producing pancreas cells were still absent after 8 years.
  • Serum fructosamine levels remained within the range that indicates good glycemic control in diabetic dogs.
  • Blood glucose levels rose slightly higher than those of healthy dogs after oral glucose challenge but returned to reference levels within 2 hours.
  • Serum total cholesterol and triglyceride levels remained within the ranges expected in healthy dogs throughout the study period.
  • No muscle inflammation or pathological glycogen accumulation in muscles was evident.
  • Postmortem analysis showed vector genomes persisted in the treated muscles 8 years after the initial administration.

“Overall, these results provide strong evidence of the persistence of vector genomes in injected dog muscles, which mediate long-term expression of therapeutic proteins for ∼8 years after a single vector administration and explain the tight control of glycemia achieved in these animals for such a long period of time,” wrote the authors.

The authors noted that this technique will need to be further developed before it can be used clinically. “Toward a future application in humans, this study demonstrates in large animals the long-term efficacy and safety of [insulin] and [glucokinase] gene transfer, and especially the adaptability of the system to the changes in metabolic needs associated with aging,” they concluded.

Six of the authors reported being inventors of patent applications related to using insulin and glucokinase to treat diabetes.

Dr. Laurie Anne Walden received her doctorate in veterinary medicine from North Carolina State University. After an internship in small animal medicine and surgery at Auburn University, she returned to North Carolina, where she has been in small animal primary care practice for over 20 years. Dr. Walden is also a board-certified editor in the life sciences and owner of Walden Medical Writing, LLC. She works as a full-time freelance medical writer and editor and continues to see patients a few days each month.

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