Gene Therapy Strategies Towards Immune Tolerance to Treat the Autoimmune Diseases

Abstract

Autoimmune diseases such as type 1 diabetes and multiple sclerosis pose a significant health burden on our society. As a whole, autoimmune diseases affect approximately 6% of the population and are the third largest disease burden after heart disease and cancer. Such pathologic manifestations arise by way of damaging reactions of B-cell derived antibodies and/or T-cells to self-antigens and are triggered by genetic and environmental factors. Currently there is no known cure, with treatment restricted to toxic, long-term immunosuppressive regimes, replacement therapy and in intractable cases, transplantation of autologous or allogeneic haematopoietic stem cells. In experimental models of autoimmunity, gene therapeutic approaches have demonstrated promise in treating the autoimmune diseases. These include delivery of anti-inflammatory cytokines and exploitation of regulatory T cells. However, none of these approaches provide lasting, long-term benefit. We hypothesise that therapeutically transduced haematopoietic stem cells followed by transplantation is an alternative strategy to establish permanent immune tolerance that can not only prevent autoimmunity but also cure these diseases. Our approach is focused on directing autoimmune disease-specific autoantigen expression in the thymus by genetic manipulation of haematopoietic stem cells to establish molecular chimeras. Our hypothesis originates from experimental studies with a mouse model of experimental autoimmune gastritis (EAG) and more recently with the non-obese diabetic (NOD) mouse model for type 1 diabetes (T1D).

Androgen depletion increases the efficacy of bone marrow transplantation in ameliorating experimental autoimmune encephalomyelitis

“…BMT combined with retroviralmediated autoantigen encoding gene transfer has the potential to reestablish tolerance to target autoantigens through induced peripheral antigen gene expression in the thymus and subsequent negative selection. 52 Mezey et al 53 demonstrated the presence of donor neuronal cells in BMT-treated leukemic patients, with the youngest patient (2 years of age at the time of BMT) having the greatest proportion of donor neuronal cells. This raises the question of whether immune regeneration by sex steroid ablation can increase the proportion of donor neuronal cells in an adult transplantation setting and subsequently enhance repopulation and regeneration of the damaged CNS.…”

Multi‐gene engineering: Simultaneous expression and knockdown of six genes off a single platform

“…Examples include proliferation control, anti-apoptosis, and bottleneck engineering to increase recombinant protein production (Fussenegger et al, 1998b;Schlatter et al, 2003;Tigges and Fussenegger, 2006), the reprogramming of desired cell phenotypes for tissue engineering (Fux et al, 2004b;Schuldiner et al, 2000), and the treatment of polygenic diseases (Bottino et al, 2003;Evans et al, 2004;Furlan et al, 2004;Siatskas et al, 2006). In some instances such applications will require the overexpression of multiple genes, others the down-regulation, and just as likely, a combination of both.…”

Adult Stem Cell Therapy for Autoimmune Disease

“…Patients with autoimmune diseases frequently have unusual antibodies circulating in their blood that target their own body tissues. As a whole, over sixty autoimmune diseases affect about 6% of the population and are the third largest disease burden after heart disease and cancer (1). Autoimmune diseases can be broadly divided into organ-specific and systemic autoimmune diseases depending on the location of the target antigen and clinical features.…”