Gene therapy in diabetes mellitus
Authors: Shaw James A. M. , Docherty Kevin 
Published: July 2011

The distinctions between what has previously been termed cell therapy and gene therapy have become blurred. Cell therapy traditionally implied the in vitro expansion of cells that could subsequently be engrafted into patients to elicit a therapeutic effect, while gene therapy was a term applied to the genetic manipulation of tissues or cells in vivo or ex vivo. With the amazing advances that have been achieved using transcription factors to reprogramme cells, this distinction, at least for regenerative medicine applications, no longer exists. In this chapter, following the statement of the unmet clinical need, we review potential sources of new β‎ cells and approaches to β‎ cell replacement therapy; discuss how recent advances in safety and efficacy of gene transfer technology can augment cellular therapeutic approaches, and summarize pure gene therapy approaches dependent on expression of genes encoding insulin and other glucose-lowering hormones in the recipient’s own cells. Since both type 1 and type 2 diabetes are associated with a decline in β‎ cell mass, cell and gene therapy targeted at the β‎ cell and insulin replacement have potential applications for both forms of the disease.

In type 1 diabetes, uninterrupted compliance with insulin injection therapy is necessary to prevent potentially fatal ketoacidosis. The landmark Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications follow-up study have confirmed that chronic hyperglycaemic microvascular and macrovascular complications can be prevented by tight glycaemic control, but this was at the expense of a threefold increase in severe hypoglycaemia—one of the greatest fears of those living with daily insulin injections. Overall, the health implications and economic costs of type 1 diabetes are massive, and increasing annually. There is, therefore, an unquestionable clinical need for new therapeutic options.

While transplantation of whole pancreas together with its blood supply can entirely normalize blood glucose levels, the major surgery required is associated with 5% mortality in the first year, even in the most experienced centres. Isolation and transplantation of purified insulin-secreting islets of Langerhans from a donor pancreas requires only minimally invasive cannulation of the portal vein transhepatically under X-ray guidance. This offers the promise of more widespread implementation restoring excellent control, preventing both long-term complications and severe hypoglycaemia. Capacity will, however, be severely limited by the scarcity of deceased donor organs: currently sufficient for fewer than 1% of those who might benefit from this form of treatment. This has provided impetus to efforts to produce a replenishable supply of glucose-responsive insulin-secreting cells that could be used in transplantation. One potential source might involve the in vitro differentiation of stem cells derived from embryonic and adult tissue.

Type 2 diabetes is marked by both a resistance of target tissue to the effects of insulin and impaired function of the β‎ cell. The major β‎-cell defects relate to an impaired secretory response to glucose, altered kinetics of secretion including pulsatility, accumulation of islet amyloid polypeptide, an increase in glucagon-secreting α‎ cells, and a decline in β‎-cell mass. Current therapy for type 2 diabetes involves a combination of drugs directed at improvements in both insulin sensitivity and β‎-cell function, together with management of associated cardiovascular risk factors. Conventional treatment modalities have not been able to prevent the inexorable progressive loss of β‎-cell function necessitating insulin replacement in the majority over time, but this is often insufficient to sustainably achieve target glucose levels outwith intensive clinical trials. It is envisaged that novel cell therapy approaches will enable restoration of β‎-cell mass.