Diabetes is a complex
metabolic disease that exposes patients to the deleterious effects of
hyperglycemia on various organs. Achievement of normoglycemia with exogenous
insulin treatment requires the use of high doses of
hormone, which increases the risk of life-threatening
hypoglycemic episodes. We developed a gene
therapy approach to control diabetic
hyperglycemia based on co-expression of the
insulin and
glucokinase genes in skeletal muscle. Previous studies proved the feasibility of gene delivery to large diabetic animals with adeno-associated viral (AAV) vectors. Here, we report the long-term (∼8 years) follow-up after a single administration of therapeutic vectors to diabetic dogs. Successful, multi-year control of glycemia was achieved without the need of supplementation with exogenous
insulin. Metabolic correction was demonstrated through normalization of serum levels of
fructosamine,
triglycerides, and
cholesterol and remarkable improvement in the response to an oral
glucose challenge. The persistence of vector genomes and therapeutic transgene expression years after vector delivery was documented in multiple samples from treated muscles, which showed normal morphology. Thus, this study demonstrates the long-term efficacy and safety of
insulin and
glucokinase gene transfer in large animals and especially the ability of the system to respond to the changes in metabolic needs as animals grow older.