Autoimmune Disorders

Autoimmune disorders encompass a group of chronic diseases affecting millions of people worldwide. These conditions occur when the immune system mistakenly attacks the body's own tissues and organs, leading to inflammation, damage, and dysfunction. Common autoimmune disorders include rheumatoid arthritis, multiple sclerosis, type 1 diabetes, systemic lupus erythematosus, and inflammatory bowel disease. Conventional treatments primarily rely on immunosuppressive drugs such as corticosteroids, cyclosporine, and methotrexate, aiming to reduce immune response activity and severity. However, these treatments have limitations like non-specificity, side effects, toxicity, and resistance. Thus, there's a pressing need for more effective and safer therapies for autoimmune disorders. Gene therapy emerges as a promising alternative, intending to correct or modulate underlying genetic defects or dysregulated immune responses in autoimmune disorders. This innovative approach involves delivering genetic material into target cells or tissues to achieve therapeutic effects. Depending on the strategy, gene therapy can edit, transfer, silence, or regulate genes involved in autoimmune disorders' pathogenesis or regulation.

Fig.1 Summary of the Development of Autoimmune Disease (Wang L, 2015)

Characteristics of Gene Therapy for Autoimmune Disorders

Gene therapy offers advantages and challenges in treating autoimmune disorders. It enables precise targeting of specific cells or tissues involved in the autoimmune response, such as T cells, B cells, antigen-presenting cells, or inflamed tissues. This specificity enhances the therapy's efficacy, reducing side effects and toxicity compared to conventional treatments. Moreover, gene therapy can yield long-term effects by modifying the genome or epigenome of target cells or tissues, inducing immune tolerance or regulation. This reduces the need for repeated drug or vector administrations, enhancing patients' quality of life. However, gene therapy faces challenges, including evading immune rejection or clearance of vectors or transduced cells by the host immune system. This can diminish therapy efficiency, duration, and cause adverse reactions. Ensuring the safety and efficacy of gene therapy requires meticulous design, optimization, and evaluation of vectors, genes, delivery methods, and outcomes. Additionally, ethical, social, and regulatory issues associated with gene therapy must be addressed before widespread application in treating autoimmune disorders. Therefore, gene therapy represents a promising yet complex and challenging approach for autoimmune disorder treatment.

Research or Clinical Progress of Gene Therapy for Autoimmune Disorders

Gene therapy has been harnessed for addressing various autoimmune disorders, employing a range of strategies and objectives. Among the autoimmune disorders, rheumatoid arthritis, a chronic inflammatory condition affecting the joints and other organs, has emerged as one of the most scrutinized. The goal of gene therapy in rheumatoid arthritis is to mitigate inflammation, alleviate pain, minimize damage, and restore joint functionality and mobility. Several gene therapy approaches for rheumatoid arthritis have been explored, including the delivery of anti-inflammatory cytokines such as interleukin-10 or interleukin-4 to synovial tissue, gene transfer encoding for immunomodulatory molecules like CTLA-4 or FasL to T cells, and gene editing targeting key players in rheumatoid arthritis pathogenesis, such as TNF-alpha or HLA-DRB1. While gene therapy for rheumatoid arthritis has demonstrated promising results in both animal models and human trials, it faces its share of challenges, including vector-related toxicity, immune responses, and gene regulation issues.

Another autoimmune disorder that has been a focus of gene therapy research is multiple sclerosis, a demyelinating disease impacting the central nervous system. The objective of gene therapy in multiple sclerosis is twofold: to prevent or reverse the loss of myelin, the protective coating of nerve fibers, and to modulate the immune system to mitigate or prevent attacks on myelin. Various gene therapy strategies for multiple sclerosis have been explored, such as the delivery of neurotrophic factors, including brain-derived neurotrophic factor or glial cell line-derived neurotrophic factor, to neurons or glial cells, the transfer of genes encoding myelin proteins like myelin basic protein or proteolipid protein to oligodendrocytes, and gene silencing targeting key genes involved in the immune response against myelin, such as CD4 or CD40. Although gene therapy for multiple sclerosis has shown promise in animal models and human trials, it grapples with challenges related to vector delivery, gene expression control, and ethical considerations.

Table 1. Examples of Gene Therapy for Autoimmune Disorders

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