TY - JOUR
T1 - Long-Term Efficacy and Safety of Insulin and Glucokinase Gene Therapy for Diabetes: 8-Year Follow-Up in Dogs
AU - Jaén, Maria Luisa
AU - Vilà, Laia
AU - Elias, Ivet
AU - Jimenez, Veronica
AU - Rodó, Jordi
AU - Maggioni, Luca
AU - Ruiz-de Gopegui, Rafael
AU - Garcia, Miguel
AU - Muñoz, Sergio
AU - Callejas, David
AU - Ayuso, Eduard
AU - Ferré, Tura
AU - Grifoll, Iris
AU - Andaluz, Anna
AU - Ruberte, Jesus
AU - Haurigot, Virginia
AU - Bosch, Fatima
PY - 2017/9/15
Y1 - 2017/9/15
N2 - 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.
AB - 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.
KW - adeno-associated viral vectors
KW - diabetes
KW - dogs
KW - gene therapy
KW - glucokinase
KW - insulin
KW - long-term
UR - http://www.scopus.com/inward/record.url?scp=85021071269&partnerID=8YFLogxK
U2 - 10.1016/j.omtm.2017.03.008
DO - 10.1016/j.omtm.2017.03.008
M3 - Article
SN - 2329-0501
VL - 6
SP - 1
EP - 7
JO - Molecular Therapy - Methods and Clinical Development
JF - Molecular Therapy - Methods and Clinical Development
ER -