GLP-1 Gene Therapy

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Glucagon-like peptide (GLP)-1 is an incretin hormone with several antidiabetic functions including stimulation of glucose-dependent insulin secretion, increase in insulin gene expression and beta cell survival. Despite the initial technical difficulties and profound inefficiency of direct gene transfer into the pancreas that seriously restricted in vivo gene transfer experiments with GLP-1, recent exploitation of various routes of gene delivery and alternative means of gene transfer has permitted the detailed assessment of the therapeutic efficacy of GLP-1 in animal models of Type 2 Diabetes (T2DM). As a result, many clinical benefits of GLP-1 peptide/analogs observed in clinical trials involving induction of glucose tolerance, reduction of hyperglycemia, suppression of appetite and food intake linked to weight loss have been replicated in animal models using gene therapy. Furthermore, GLP-1-centered gene therapy not only improved insulin sensitivity, but also reduced abdominal and/or hepatic fat associated with obesity-induced T2DM with drastic alterations in adipokine profiles in treated subjects. Thus, a comprehensive assessment of recent GLP-1 mediated gene therapy approaches with detailed analysis of current hurdles and resolutions are discussed.

Figure 1 Major antidiabetic properties of GLP-1. GLP-1 is released from intestinal L cells located in the lower intestine (ileum). Target organs include, but not limited to, pancreas, liver, stomach, muscle, adipose tissue and brain. GLP-1 also suppresses glucagon secretion from alpha cells, and stimulates somatostatin secretion from pancreatic delta cells. In addition, GLP-1 reduces gastric acid secretion. The effects of GLP-1 on adipose and muscle tissue (enhancement of glucose update and glycogen synthesis) are omitted for clarity.

Figure 2 Differential proglucagon processing in the intestine versus pancreas. Proglucagon is processed to generate glicentin, GLP-1(1-37) and/or GLP-1(1-36) amide, Intervening Peptide 2 (IP2) and GLP-2 by the action of PC1/3 in the intestine. PC1/3 can further process glicentin and GLP-1 to produce oxyntomodulin and GLP-1(7-37) and/or GLP-1(7-36) amide. PC2 processing of proglucagon fragment in pancreatic alpha cells yields Glicentin Related Pancreatic Polypeptide (GRPP), glucagon, IP-1, and the major proglucagon fragment rather than GLP-1.

Figure 3 Gene therapy vector design encoding GLP-1. A cell type-specific promoter (e.g., insulin promoter) restricts transgene expression in target tissues. Epitope targeting by way of pseudo-typing or use of alternative serotypes of viral vectors is also employed to achieve tissue specificity. A variety of signal peptides are employed to direct GLP-1 into secretory pathways. Furin cleavage is necessary to remove GLP-1 from the signal peptides. The Ala to Gly substitution in GLP-1 provides resistance to DPP-4 cleavage. Alternative routes of gene delivery through celiac artery by transient blockage of splenic and hepatic arteries also provide efficient islet transduction by viral vectors.

Concluding remarks: Viral or non-viral gene delivery methods have been under development to supply a constant GLP-1 production and secretion for the treatment of diabetes, since GLP-1 must be delivered through a parenteral route and has a short lifespan. Even though gene therapy appears to be a promising technique for achieving a long-term increase in GLP-1 synthesis and secretion, the most effective gene delivery method has yet to be identified. Protocols using dsAAV vectors have produced some successful results, similar or enhanced results are expected using lentivirus vectors targeting pancreas with glucoregulatory function. This is especially true when the long-term beneficial neuroprotective and/or cardioprotective effects of GLP-1 are expected. GLP-1 gene delivery has produced favorable results in both pre-diabetic and fully diabetic animals, suggesting that a GLP-1 gene therapy approach may be a reasonable alternative to constant infusions or daily injections of GLP-1 peptide. It is important to keep in mind, though, that many of these published results showing the benefits of GLP-1 gene therapy were conducted in small rodent models of T2DM, making it crucial to continue testing of this therapy in larger animal models (such as cats, dogs, pigs, and even primates) to increase the clinical relevance of experimental findings and design future clinical trials.