Gene Therapy for Type-1 Diabetes

Introduction.

Type-1 diabetes is a chronic disease resulting from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Although progress has been made toward improving diabetes-associated pathologies and the quality of life for those living with diabetes, no therapy has been effective at eliminating disease manifestations or reversing disease progression. Therefore, novel therapeutic approaches are currently being sought. Among the approaches with the most promise is gene therapy.

Background on the Disease.

Type-1 diabetes (T1D), also known as insulin-dependent diabetes mellitus, is recognized as a rapidly growing health threat worldwide. The CDC estimates that 15,000 young people in the United States per year are diagnosed with T1D, with 19 new cases per 100,000 youth each year

Existing Therapies.

T1D patients require lifelong insulin replacement therapy, and are at risk of developing significant complications associated with hyperglycemia, such as retinopathy, neuropathy, nephropathy, and accelerated peripheral vascular and coronary artery disease. The goal of existing therapy is to provide tight glycemic control in all diabetic patients in order to minimize the complications associated with hyperglycemia.

Furthermore, while allogeneic islet transplantation has shown some evidence of success, the allo- and autoimmune response against the islets often leads to their destruction

Overview of Preclinical Gene Therapy Studies.

Until recently, gene therapy studies for T1D had focused primarily on ex vivo approaches to modify islets for transplantation. Although many different approaches have been examined, the goals of these modifications are similar: to transfer a gene encoding a protein which would confer some type of islet-protective effect to the grafted islets in order to protect them from allo- and autoimmune attack when transplanted into the patient. When successful, this prolongs graft survival and may potentially reduce the need for systematic immunosuppressive therapy to prevent loss of the graft. Some lingering concerns with the use of transduced islets are safety and efficacy. Particular concerns include whether expression of virally-encoded proteins from the islets will have some effect on the cellular function of the transplanted cells or immunological function of the patient receiving the graft.

Another major focus of ex vivo gene therapy strategies for T1D has been in the modification of immunological cells to promote tolerance upon adoptive transfer in vivo. Dendritic cells have been of particular interest for applications in T1D because of their unique role in regulating T cell responses. Both adenoviral and lentiviral gene transfer of IL-4 to DC have been shown to have protective effects in the NOD model of T1D

Overview of Clinical Gene Therapy Studies.

To date, few proposed gene therapy strategies for T1D have progressed to the point of clinical trials. A Phase I clinical trial to examine safety is currently ongoing using DC genetically modified using antisense oligonucleotides (AS-ODN) to the costimulatory molecules CD40, CD80, and CD86. In preclinical studies using the NOD mouse model of T1D, investigators demonstrated that the AS-ODN treated bone-marrow derived DC were able to delay the incidence of diabetes after a single injection, and observed that the AS-ODN treated DC resulted in an expansion of a CD4+CD25+CD62L+ regulatory T cell population

Conclusions.

Considerable progress has been made towards developing gene therapy approaches for T1D, leading to the development of some phase I clinical trials. Because this disease does not respond well to present biologics, the development of alternative approaches, such as gene therapy, seems highly appropriate. Overall the technology of gene transfer, along with efficacy of gene therapy in animal models of autoimmune diseases, such as T1D, has developed to the point where it is no longer the rate limiting step for many purposes. Instead, the focus of the field of gene therapy for autoimmune diseases is now on bringing these approaches into the clinic.

References.