Long-Term Efficacy and Safety of Insulin and Glucokinase Gene Therapy for Diabetes: 8-Year Follow-Up in Dogs

Abstract

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.

Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways

“…The total dose of vectors was distributed between the gastrocnemius muscles of both hind limbs. AAV transduction of non-dividing cells, such as the skeletal muscle cells and liver cells, is predominantly non-integrative and supports long-term transgene expression, as demonstrated in studies with experimental animals Bernardes de Jesús et al, 2012;Binny et al, 2012;Callejas et al, 2013;Haurigot et al, 2010;Jaén et al, 2017;Nathwani et al, 2011) and in clinical studies (Buchlis et al, 2012;Nathwani et al, 2014).…”

FGF21 gene therapy as treatment for obesity and insulin resistance

“…Skeletal muscle (Skm) is a readily accessible tissue and has been used to produce secretable therapeutic proteins (Haurigot et al , ; Callejas et al , ; Jaén et al , ). To explore whether the Skm could represent a viable source of circulating FGF21, AAV vectors of serotype 1, which show a high tropism for Skm (Chao et al , ; Wu et al , ; Lisowski et al , ), carrying murine optimized FGF21 under the control of the CMV promoter were used (AAV1‐CMV‐FGF21).…”

Five Years of Successful Inducible Transgene Expression Following Locoregional Adeno-Associated Virus Delivery in Nonhuman Primates with No Detectable Immunity

“…The highest number of long-term reports (between 2.5 and 6 years post injection) has been provided for gene transfer studies targeting the relatively immune-privileged retina and the central nervous system in NHP and canine models. [29][30][31] With regard to systemic, i.m., or intrahepatic routes, there are now also numerous promising long-term reports (between 2 and 8 years post injection) in NHP 32 and canine models for diabetes, 33 metabolic diseases, 34 hemophilia, 35,36 or muscular dystrophies. 37,38 Moreover, the field now has the benefit of up to 10 years of hindsight in humans with persisting gene transfer following one single injection.…”