Development of gene transfer for induction of antigen-specific tolerance

Abstract

Gene replacement therapies, like organ and cell transplantation are likely to introduce neo-antigens that elicit rejection via humoral and/or effector T cell immune responses. Nonetheless, thanks to an ever growing body of pre-clinical studies it is now well accepted that gene transfer protocols can be specifically designed and optimized for induction of antigen-specific immune tolerance. One approach is to specifically express a gene in a tissue with a tolerogenic microenvironment such as the liver or thymus. Another strategy is to transfer a particular gene into hematopoietic stem cells or immunological precursor cells thus educating the immune system to recognize the therapeutic protein as “self”. In addition, expression of the therapeutic protein in pro-tolerogenic antigen presenting cells such as immature dendritic cells and B cells has proven to be promising. All three approaches have successfully prevented unwanted immune responses in pre-clinical studies aimed at the treatment of inherited protein deficiencies, e.g. lysosomal storage disorders and hemophilia, and of type I diabetes and multiple sclerosis. In this review we focus on current gene transfer protocols that induce tolerance, including gene delivery vehicles and target tissues, and discuss successes and obstacles in different disease models.

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease

“…50 Therefore, developing immune tolerance induction strategies to be combined with gene therapies is at the forefront of investigation for Pompe disease and similar diseases that undergo protein replacement therapies. 20 In this work, we provide evidence that both disease-related functional deficits and immune tolerance can be simultaneously addressed using AAV9-mediated GAA expression. Gaa -/-mice intravenously treated with a copackaged AAV9 vector, containing a liver-specific expressing vector as well as a vector with tissue-restricted specificity, attenuated skeletal muscle and cardiac pathology while providing antigen-specific tolerance.…”

“…Although clinical management of the immune response is feasible with B-and T-cell modulation using immunosuppressive agents (such as rituximab, sirolimus, or methotrexate), long-term immune tolerance induction established through gene therapy stands as a more attractive means to prevent these responses. 8,20 All recessive conditions face limitations inherent to gene replacement strategies when there is no residual endogenous protein expressed. Pompe disease is a strong candidate for gene therapy given the response to ERT.…”

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

“…Other recent approaches for the induction of specific immune tolerance include the use of synthetic nanoparticles containing specific proteins in combination with immunosuppressive drugs (Maldonado et al, 2014), stem cell transplantation (Coleman and Steptoe, 2012) and gene transfer (Sack et al, 2014).…”

A genome editing primer for the hematologist

“…[78][79][80] Even if a mutant gene were effectively repaired or replaced, an additional challenge may be to avoid immune responses against the novel gene product. 81 Although gene correction might seem the most intuitive approach to therapeutic genome editing, in fact the first clinical trial using targeted nucleases in human patients has relied on NHEJ-based genetic disruption rather than gene repair. One advantage of this strategy is that NHEJ tends to be a more active repair pathway compared with HDR, particularly in quiescent cells.…”