Gene and Cell-Replacement Therapy in the Treatment of Type 1 Diabetes

Abstract

Recent advances in molecular and cell biology may allow for the development of novel strategies for the treatment and cure of type 1 diabetes. In particular, it is now possible to envisage restoration of insulin secretion by gene or cell-replacement therapy. The ␤-cell is, however, remarkably sophisticated, and many of the features of this highly differentiated secretory cell will have to be faithfully mimicked in surrogate cells. In particular, insulin is normally secreted in a well-regulated fashion in rapid response to the metabolic needs of the individual and most specifically (but not exclusively) to changes in circulating levels of glucose. Such regulated secretion will be indispensable in order to avoid both hyper-and hypoglycemic episodes and depends on the ability of cells to store insulin in secretory granules before exocytosis in response to physiological stimuli. Furthermore, any newly created insulin-secreting cell will have to be able to adapt to alterations in insulin requirements that accompany changes with exercise, body weight, and aging. Fine tuning of insulin secretion over the longer term will also be important to avoid "clinical shifting" that could be caused by overinsulinization, including increased adiposity and cardiovascular disease. Finally, it will be necessary to ensure that newly created or implanted (surrogate) ␤-cells are protected in some way from recognition by the immune system and in particular from autoimmune destruction. Diabetes 50:2181-2191, 2001 R ecent success in reversing type 1 diabetes by islet transplantation, as reported by the Edmonton group (1), has led to renewed optimism in the field. It is, however, quite apparent that human islets will never be available in sufficient numbers to satisfy the needs of all the patients in the world with diabetes. Furthermore, islet transplantation still requires long-term (and most likely life-long) immunosuppression. A seductive means of circumventing both of these obstacles would be by gene therapy or by cell-replacement therapy, two possible approaches for replacing endogenous insulin production that we have defined below. Our intention in this article is to place these two methods in as objective a setting as possible and to set minimal standards that we feel need to be met in order for them to be useful in a clinical setting. It is not our purpose to write a comprehensive review of the field, and we do not wish to take sides on any of the issues discussed. Our motivation is straightforward but strongly felt. We are particularly dismayed by the increasing number of papers, more often than not published in highly reputable (and on occasion in widely distributed) journals, claiming to be on track to a cure for diabetes by means of gene or cell therapy. These papers are often misleading, and those misled, given the attention such papers receive in the lay press and on television, are first and foremost patients with diabetes and their families. We encourage everyone to review all papers in this area of research with a critical ...

Impact of integrin-matrix matching and inhibition of apoptosis on the survival of purified human beta-cells in vitro

“…Targeted intervention in apoptotic and/or oxidative stress and inflammatory signalling pathways could be one such approach. Such methodology will also be essential, in our opinion, for obtaining the large numbers of highly differentiated insulin-secreting cells envisaged for cell replacement therapy [44] regardless of whether they have been derived by conditional immortalisation of beta cells [4,5], from adult [6] or embryonal [7,8,9] stem cells or by any other means for creating surrogate beta cells.…”

Efficient restricted gene expression in beta cells by lentivirus-mediated gene transfer into pancreatic stem/progenitor cells

“…Replacement of insulinproducing tissue by transplantation of mature beta cells represents an effective method of curing type 1 diabetes. However, many obstacles remain before cell replacement therapy [1] can be used routinely to treat diabetic patients [2]. The major issues to be solved are allorejection, recurrence of anti-islet cell autoimmunity and the shortage of available donor tissue.…”

Vectors for the treatment of autoimmune disease

“…In comparison, secretion of endogenous insulin from b islet cells occurs within approximately 20 min after glucose uptake. This discrepancy in response kinetics was considered at length in a recent review by Halban et al 181 Although not strictly a vector component, and therefore outside the remit of this review, there is an innovative system through which protein secretion can be rapidly regulated in a pharmacological manner, which has the potential to provide an alternative mechanism to regulate the activity of a therapeutic protein. 182 The system is based on the fact that a single mutation (Phe 36 -Met) converts a monomeric human protein FKBP12 into a conditional aggregation domain termed F M that forms dimers with micromolar affinity that are completely dissociated by small synthetic ligands.…”