Gene therapy in immune-mediated diseases of the eye

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Abstract

Therapy of ocular immune-mediated diseases has changed dramatically over the past two decades. Although a variety of non-specific immunosuppressive agents are introduced, with advances in cell biology a number of more specific therapeutic options will become available. Gene therapy has the potential to interfere with the immune response at different steps modulating the microenvironment of the eye. In this chapter we focus attention on the most promising candidate genes for gene therapy in ocular immune diseases. Furthermore, we outline the current techniques for delivering genes of interest with their potential merits and drawbacks in the field of ophthalmology. Many of these approaches are still in early phases of study for the treatment of clinical relevant immune-mediated diseases.

Introduction

It has been recognized for more than 100 years that the eye is an organ prone to immune-mediated diseases. Despite a range of mechanisms that protect the delicate organ against exogenous and endogenous pathogens, inflammatory and immune-mediated processes are a leading cause for blindness (Thylefors et al., 1995). They may affect all compartments and structures of the eye and vary from “allergic” conjunctivitis to infectious associated keratitis and intraocular inflammation. Immunotherapy to affect or modulate the immune system may induce a change in the expression of disease and provide effective strategies for the management of potential blinding diseases. A number of “classical” agents ranging from corticosteroids, immunophilin ligands (Cyclosporin A, Tacrolimus), to cytotoxic agents such as cyclophosphamide have moved to the clinical arena (Sherif and Pleyer, 2002). However, even when enormous progress has been achieved in the field of immunopharmacology, several disadvantages still remain. Currently available immunosuppressive agents have modest selectivity, limited efficacy and still considerable toxicity. Since in almost all immune-mediated conditions long-term treatment is required, undesired side effects are a constant treath for the patient and therefore further therapeutic options are necessary.

Significant progress has been made in the understanding of basic biology in particular of the immune regulatory network and this may soon turn to medical advantage. A number of new approaches are still in early phases of study for the treatment of clinical relevant immune-mediated diseases. One of the most recent advances in this respect is the introduction of gene therapy. Most of these strategies seek to transfer genes encoding immunomodulatory products that will alter the host immune response in a beneficial manner. By this means gene therapy overcomes obstacles to the targeted delivery of proteins and RNA, and improves their efficacy while providing a longer duration of effect, and, potentially, greater safety. Additional genetic strategies include DNA vaccination and the ablation of selected tissues and cell populations. There is considerable evidence from animal studies that gene therapies work: examples include the treatment of experimental models of rheumatoid arthritis, multiple sclerosis, diabetes, and lupus erythematodus. Up today, more than 400 clinical studies have been performed or are in process (Human Gene Transfer Protocols, 2002; Costa et al., 2000; Seroogy and Fathman, 2000; Evans et al., 2000). However, so far limited experience has gained in respect of gene therapy in ocular diseases, despite the fact that the eye might be even “an ideal organ” providing several unique advantages including

  • a significant number of ocular diseases have been delineated at the molecular level,

  • there are appropiate animal models available,

  • the morphology and function of the eye is relatively easy to evaluate,

  • the “immune-privileged” status of the eye is in advantage to the development of gene therapeutic approaches,

  • as a paired organ the eye holds the opportunity that the second eye can be used as an “internal control”.

This chapter is intended not only to provide an overview on the use of gene therapy in the setting of ocular immune-mediated diseases but also to introduce this application in broader respect and to stimulate interest in this field.

Section snippets

Principles of the immune response

The immune system plays a central role in maintaining homeostasis and health, although it may also cause pathologic reactions to the host in response to exogenous or endogenous pathogens. Immune effector functions can be broadly divided into two types, cell mediated and humoral. Cell-mediated immune responses include the presentation of a pathogen by specialized antigen presenting cells (APC) such as dendritic cells and activation of macrophages with the induction of cytotoxic CD8+ and CD4+ T

Gene therapy — an introduction

The tremendous advances in molecular medicine and biology within the last decades have led to the development of promising therapeutic tools for the treatment of cancer, genetic defects, infectious diseases or autoimmune disorders. These include the generation of gene-based approaches, e.g. for the correction of defective genes or the over-expression of therapeutic molecules. Despite enormous efforts and funding which have been put in the development of gene-based therapies the success of these

Autoimmune diseases

Background. Activation of T cells by self-antigens is under strict control by different mechanisms, both thymic and peripheral. Failure of these mechanisms controlling tolerance to self-antigens may lead to autoimmunity. One of the striking characteristics of autoimmune diseases is the increased frequency of alleles for specific human leukocyte antigens (HLAs) in affected individuals. It seems likely that disease associated HLA molecules have the capacity to bind the antigen and present it to T

Infectious diseases

Despite the success in developing antiviral treatment, gene therapy is considered as an alternative approach particular in patients non-responding to conventional drug therapy. According to Bunnell and Morgan, gene therapy of infectious diseases can be divided into three broad categories:

  • (1)

    gene therapy based on nucleic acids (e.g. antisense DNA/RNA, RNA-decoys, ribozymes);

  • (2)

    protein-based approaches (e.g. expression of anti-infectious cellular proteins or intrabodies);

  • (3)

    immunotherapeutic approaches

Current problems and further directions

As already indicated, the induction of an antiviral immune response is still one of the major unsolved problems in gene therapy. These immune responses include both cells from the innate immune system (e.g. dendritic cells, macrophages as early defense strategy by the host) as well as components from the aquired immune system (B cells, T cells) (Bromberg and Debruyne, 1998; Brenner, 1999; Kay et al., 2001; Ritter et al., 2002) (Fig. 5). However, there is a clear hierarchy in the severity of

Acknowledgements

The authors like to thank Drs. Mel Trousdale, M.D., Doheny Eye Institute, Los Angeles, CA, USA, and Hans-Dieter Volk, M.D. Institute of Medical Immunology, Charité, Humboldt-University Berlin, Germany, for critically reading this manuscript.

This work was supported in part by a grant of Deutsche Forschungsgemeinschaft (DFG Pl 150/10-2) and (DFG Ri 764/6-1).

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    Supported in part by Deutsche Forschungsgemeinschaft (Pl 150/10-1 and Ri 764/6-1).

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