Gene Therapy for Autoimmune and Inflammatory Diseases


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Biomedical Sciences Human Genetics. Milestones in Drug Therapy Free Preview. Buy eBook. Buy Hardcover. Buy Softcover. FAQ Policy. About this book In this monograph about gene therapy of autoimmune and inflammatory d- orders we have gathered international experts and leaders from different fields to review the state of the art advances on topics ranging from disease entities to vectors and engineered cells. Show all. Table of contents 15 chapters Table of contents 15 chapters Gene therapy for arthritis Pages Apparailly, Florence et al.

Gene therapy for the treatment of inflammatory bowel disease Pages Ruffner, Melanie A. Gene therapy for diabetes Pages Noguchi, Hirofumi. Gene therapy of multiple sclerosis Pages Furlan, Roberto et al. Gene therapy for myositis Pages Jung, Hans H. They also had the earmarks of a much-reduced inflammatory autoimmune reaction to the novel for them normal version of the protein.

It now looks as if the concept may hold for gene therapy, too. Advanced features of this website require that you enable JavaScript in your browser. Thank you! From our release: '[I]t seems we can induce tolerance to a wide assortment of formerly immunogenic proteins by inserting the gene for the protein of interest into the plasmid,' Steinman said. At the same time, the nonproliferative, dormant phenotype of cancer cells from different primary tumors can be overwritten by the microenvironmental properties i.

From a therapeutic point of view, it is possible to induce differentiation of cancer cells before and during chemotherapy. While this strategy can be effective in treating hematological cancers e. These cells are artificially created from nonpluripotent cells. They are typically generated from mature somatic cells by the induction of genes that determine the stem cell phenotype[ 25 ].

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The enemy within? New perspectives on autoimmune disease

In many respects such as expression of stem cell specific genes and proteins, chromatin methylation pattern, cell duplication time, creation of embryo-like body, formation of teratomas and viable chimeras these cells are similar to natural pluripotent stem cells, such as embryonic stem cells[ 25 - 27 ]. The emergence of human induced pluripotent stem cells is an important step in stem cell research, as the method allows the development of pluripotent stem cells without sacrificing of embryos, graft-versus-host disease, and immunological rejection.

Induced pluripotent stem cells have already been used for drug development and modeling of many diseases and will be beneficial in transplant medicine[ 25 - 27 ]. However, induced pluripotent stem cells may also present a risk that may limit their clinical use. Genetically modified adult cells may increase expression of protumor genes and oncogenes.

There are, however, methods that can eliminate oncogenes after induction of pluripotence and even induce pluripotent stem cells without genetic alteration of adult stem cells so-called protein-induced pluripotent stem cells [ 25 - 28 ]. From a clinical and research point of view, stem cells can be used for drug research and toxicity studies, development and gene regulation studies, genetic modification of laboratory and farm animals i.

In terms of their clinical applicability including in autoimmune disorders, cell replacement procedures and therapies that alter the natural course of diseases should be considered. The idea of using stem cells as a paradigm for replacing damaged tissues with impaired function was first introduced after World War II. Essentially, experiments that led to the fight against radiation injury were the basis for the practical applicability of stem cells.

To date, stem cell therapy has become an alternative experimental tool, not only for the treatment of malignant hematological diseases and bone marrow failure, but also for almost all other systemic diseases[ 6 , 29 ]. Certain stem cells possess the specific ability to alter the cellular response to injury or abnormal immune activity in the absence of being incorporated into the recipient's organism.

These stem cells act on the outcome of the disease without directly replacing the damaged cells. Bone marrow mesenchymal stem cells were initially believed to promote tissue regeneration by direct cell replacement; however, these cells stimulate tissue repair mainly by paracrine control signals. The mesenchymal stem cell population by altering immune functions can modify the response to injuries and can alleviate the mainly inflammatory consequences of autoimmune processes[ 6 , 7 , 12 ].

From a clinical point of view, the use of stem cells is more advantageous than differentiated cells because they can be collected more easily and in larger quantities, their proliferation capacity is more pronounced, they are more resistant in cell culture, their aging is delayed, they are able to form a number of cell lines, and they are able to promote vascularization of tissue carriers[ 29 ].

Clinically, many arguments support the therapeutic use of adult stem cells.

Autoimmune and Inflammatory Diseases

They are present in virtually all organs and body fluids and can be isolated and used in an autologous manner. In adult stem cells, similarly to stem cells derived from extrafetal tissues, there is a low risk of mutation-dependent side effects. On the other hand, the clinical applicability of adult stem cells, in contrast to the ethical and legal norms regulating the use of stem cells from human ova, embryos, and fetuses, is considerably more relaxed[ 1 , 6 , 29 ].

While storing stem cells derived from extrafetal tissues provides the opportunity for future regenerative therapy, the relatively high costs, the limited storage capacity, and the time-dependent loss of cell viability has not allowed the method to spread in developed countries. Such stem cells are mainly suitable for allogeneic use. Although the immunogenicity of stem cells, apart from induced pluripotent stem cells, is generally low, the potential immunological response to an allogeneic graft may require immunosuppressive treatment. For the time being the use of adult stem cells seems more advantageous for both cell therapy and tissue formation[ 29 ].

A-K: Profiles of Faculty Working on Autoimmune and Inflammatory Diseases

It is also important to emphasize that the regenerative capacity of tissue-specific progenitor cells is affected by both the natural process of aging and many diseases e. The stem cell properties of progenitor cells may be adversely influenced by genomic instability, telomere shortening, epigenetic differences, loss of protein balance, nutrient deficiency, mitochondrial dysfunction, and intercellular communication disorders[ 30 ].

In the following, we summarize the clinical results of stem cell therapy in select autoimmune diseases. Between and , around bone marrow transplantations were performed in autoimmune and autoinflammatory diseases worldwide. Preclinical studies in animal models of genetically determined e.

In autoimmune diseases in the introductory phase of HSCT, intensive immu-nosuppression for the elimination of autoreactive lymphocytes is clinically useful. HSCT is believed to permanently alter the immune system by losing T-cell mediated immunological memory[ 30 , 31 ] Figure 1. Table 1 summarizes the indication of stem cell transplantation in autoimmune and autoinflammatory diseases European Bone Marrow Transplantation Recom-mendation In most systemic sclerosis SSc patients, conventional therapeutic agents are less effective.

The selection criteria of patients with predominantly diffuse cutaneous SSc were the same, but the duration of conditioning treatments, stem cell mobilization and selection techniques, and follow-up were different in each study.

Emerging Arrhythmic Risk of Autoimmune and Inflammatory Cardiac Channelopathies

All in all, the results are promising. In The Scleroderma: Cyclophosphamide Or Transplantation Trial study, skin condition and lung function improved after HSCT compared to patients with standard treatment in which the disease progressed. On the other hand, long-term follow-up of patients undergoing HSCT is mandatory in order to identify potential serious complications such as secondary autoimmune diseases, malignant tumors, cardiovascular consequences in a timely manner[ 31 , 32 ].

The goal is to make HSCT available as early as possible in the course of the disease. Although initial results are encouraging because there was complete symptom relief in the case of a positive therapeutic response , the remission-inducing effect of HSCT in SLE requires further testing. The previous studies are far from sufficient. The number of patients enrolled in the studies was low, and the patients formed a heterogeneous group, both clinically and in terms of immunosuppressive treatment and HSCT methods. Furthermore, the effect of the so-called publication bias is not negligible i.

Although the combination of autologous HSCT with fludarabine and anti-CD20 therapy appears to be beneficial, it is important to note that many infections and other adverse events occurred in patients receiving high-dose immunosuppression prior to stem cell transplantation[ 34 , 35 ]. The aim is to compare the therapeutic efficacy of HSCT with the best available standard treatment options including rituximab therapy[ 36 ].


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Although autologous HSCT is a theoretically accepted therapeutic alternative in SLE and APS patients, it is currently only referred to as salvage therapy in severe, refractory cases[ 33 , 36 ]. Based on a limited number of studies, allogeneic HSCT may be the only curative therapeutic option through reprogramming the immune system[ 37 ]. In the absence of a suitable donor or severe co-morbidity, autologous HSCT is recommended[ 38 ].

Autologous HSCT has been investigated in many studies in rheumatoid arthritis patients who do not respond to conventional treatments. Yet, the latest, effective biological treatments in rheumatoid arthritis have reduced the use of autologous HSCT[ 31 - 33 , 35 ]. Autologous HSCT has been used primarily in children with systemic juvenile idiopathic arthritis. There is only limited data available on HSCT treatment in the heterogeneous group of vasculitides.

Because of relapse, 3 patients received another transplant. Unfortunately, 3 patients died[ 33 ]. According to prospective studies and case reports, the autologous HSCT in Crohn's disease is a suitable method for achieving remission. However, for 45 patients enrolled in the Autologous Stem Cell Transplantation for Crohn Disease study, the results were not convincing.

According to the official European Crohn's and Colitis Organization recommendation, HSCT should only be considered for Crohn's disease patients with severe illness accompanied by active luminal inflammation and refractory to any available medication, and surgery alone is not enough Figure 2. During autologous HSCT, significant regeneration of circulating T cell clones results in immunological resetting. Multiple sclerosis is categorized into four types: rapidly aggravating, relapsing-remitting, secondary progressive, and primarily progressive.

Various autoimmune diseases have occurred in most autologous HSCT patients with multiple sclerosis. In the early stages of the disease, autologous HSCT performed in relapsing-remitting types is more effective than in severe progressive cases[ 33 , 36 ]. In the chronic inflammatory demyelinating polyneuropathy patients who require long-term high-dose immunosuppressive therapy, initial experience with autologous HSCT is hopeful. In Europe, nearly 30 patients underwent intervention, with a clear positive trend in their neurological status.

Despite encouraging clinical efficacy and apparent safety, the biological mechanisms explaining the therapeutic effect of mesenchymal stem cells in SLE have not yet been elucidated[ 35 , 40 ]. For SSc, there are only a small number of case reports suggesting that the use of mesenchymal stem cells is safe and effective, but comprehensive clinical trials have not yet been conducted. In severe refractory rheumatoid arthritis, two studies have been investigated for the therapeutic use of intravenously administered bone marrow-derived mesenchymal stem cells.

Based on the results, the method was safe, no serious adverse effects occurred, and clinically significant remission was observed. Three to six months after the intervention, the level of inflammatory cytokines in the peripheral blood decreased and the number of Treg cells increased. Mesenchymal stem cells derived from adipose tissue have been shown to have similarly good results, but in order to maintain the therapeutic effect, the introduction of stem cells was repeated every 3 mo[ 35 , 41 ].

Fifty percent of patients with Crohn's disease were in remission after half a year with parenteral administration of mesenchymal stem cells isolated from placenta.

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At the same time, by increasing the number of stem cells administered, only one-third of the patients had an appreciable therapeutic effect, and after 6 mo none of them were in remission[ 42 , 43 ]. In summary, the progress in clinical trials using stem cells for disease modification, immunomodulation, or regenerative purposes are undoubtedly encouraging, but most are still in the early stages, and the clinical results reported are not clear about therapeutic efficacy and potential side effects.

Uniform regulation of the clinical application of stem cells is also indispensable for this highly customizable, minimally invasive, and individualized therapeutic method to become a successful and safe treatment alternative in many different disorders.

Gene Therapy for Autoimmune and Inflammatory Diseases Gene Therapy for Autoimmune and Inflammatory Diseases
Gene Therapy for Autoimmune and Inflammatory Diseases Gene Therapy for Autoimmune and Inflammatory Diseases
Gene Therapy for Autoimmune and Inflammatory Diseases Gene Therapy for Autoimmune and Inflammatory Diseases
Gene Therapy for Autoimmune and Inflammatory Diseases Gene Therapy for Autoimmune and Inflammatory Diseases
Gene Therapy for Autoimmune and Inflammatory Diseases Gene Therapy for Autoimmune and Inflammatory Diseases

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