Experimental therapies for psoriasis

There is a high medical need for better therapies for psoriasis. Based on new insight into the pathophysiology of this frequent immune disease, a number of novel systemic immunomodulatory therapies are currently in clinical development. These include approaches targeting antigen presentation and costimulation, T cell activation and leukocyte adhesion, action of proinflammatory mediators, and modulating the cytokine balance. Although mainly only preliminary data are available so far, these trials contribute to a further understanding of the disease and will eventually lead to new therapeutic options for psoriasis. Moreover, since psoriasis can be considered as a visible model disease for T cell-mediated disorders characterized by a type 1 cytokine pattern in general, such approaches may have impact for other immune disorders as well. Here we review the rationale and the initial clinical data of these important recent experimental therapies.     

Targeting leukocyte integrins in human diseases

As our understanding of integrins as multifunctional adhesion and signaling molecules has grown, so has their recognition as potential therapeutic targets in human diseases. Leukocyte integrins are of particular interest in this regard, as they are key molecules in immune-mediated and inflammatory processes and are thus critically involved in diverse clinical disorders, ranging from asthma to atherosclerosis. Antagonists that interfere with integrin-dependent leukocyte trafficking and/or post-trafficking events have shown efficacy in multiple preclinical models, but these have not always predicted success in subsequent clinical trials (e.g., ischemia-reperfusion disorders and transplantation). However, recent successes of integrin antagonists in psoriasis, inflammatory bowel disease, and multiple sclerosis demonstrate the tremendous potential of antiadhesion therapy directed at leukocyte integrins. This article will review the role of the leukocyte integrins in the inflammatory process, approaches to targeting leukocyte integrins and their ligands, and the results of completed clinical trials.     

Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer's disease

Alzheimer's disease (AD) is one of the most important neurodegenerative disorders, bringing about huge medical and social burden in the elderly worldwide. Many aspects of its pathogenesis have remained unclear and no effective treatment exists for it. Within the past 20 years, various mice models harboring AD-related human mutations have been produced. These models imitate diverse AD-related pathologies and have been used for basic and therapeutic investigations in AD. In this regard, there are a wide variety of preclinical trials of potential therapeutic modalities using AD mice models which are of paramount importance for future clinical trials and applications. This review summarizes more than 140 substances and treatment modalities being used in transgenic AD mice models from 2001 to 2011. We also discuss advantages and disadvantages of each model to be used in therapeutic development for AD.     

Autoimmune diseases of the peripheral nervous system

Autoimmune-mediated diseases targeting the peripheral nerve represent a group of disorders often associated with high clinical disability. At present, therapeutic options are limited. The application of innovative and cutting-edge technologies to the study of immune-mediated disorders of the peripheral nervous system (PNS) have generated a better understanding of underlying principles of the organization of the immune network present in the peripheral nerve and its dialogue with the systemic immune system. These insights may foster the development of specific and highly effective therapies for autoimmune diseases of the peripheral nerve. Of great interest in this context is the application of monoclonal antibodies, such as rituximab or alemtuzumab, which in small observational studies provided promising clinical results. But also other immunomodulatory or immunosuppressive drugs used in other indications currently find their way to PNS autoimmunity. Clearly, prospective controlled clinical trials are warranted before making firm conclusions on the feasibility of these innovative therapeutic approaches for treating immune-mediated disease of the peripheral nerve.     

Immunomodulators for asthma

New information regarding the molecular mechanisms of allergic disorders has led to a variety of novel therapeutic approaches. This article briefly reviews the pathogenesis of asthma and allergic diseases, discusses the rationale behind using immunomodulators in these diseases; and examines the therapeutic effects of immunomodulators on allergic diseases. There are a number of immunomodulators that have been developed for the treatment of allergic disorders. Some have looked very promising in pre-clinical trials, but have not shown significant benefits in human clinical trials thus indicating the disparity between mouse models and human asthma. This review focuses on immunomodulators that are in human clinical trials and not molecules in pre-clinical development.     

Potential off-label use of infliximab in autoimmune and non-autoimmune diseases: a review

TNF-alpha is a crucial cytokine in the establishment and maintenance of inflammation in multiple autoimmune and non-autoimmune disorders. A number of large placebo-controlled trials have shown that infliximab, a chimeric monoclonal antibody against TNF-alpha, is effective and well-tolerated in patients with Crohn's disease and rheumatoid arthritis (RA) and has become a widely used treatment for these diseases. More recent controlled trials have also shown the effectiveness of TNF-alpha blockers in psoriasis, psoriatic arthritis, and ankylosing spondylitis. The results of clinical trials, open-label studies, and case studies indicate that TNF inhibitors (alone or in combination with other protocols) look very promising for the treatment of a variety of other conditions, including uveitis, sarcoidosis, Sj?gren's syndrome (SS), Behcet's syndrome, vasculitis, and graft versus host disease. There is a rationale for using TNF blockade even in systemic lupus erythematosus, a prototype of autoantibody-mediated disease, and a pilot study seems to confirm this potential effective approach. The neutralisation of TNF might therefore play a role in the treatment of many autoimmune and non-autoimmune disorders other than Crohn's disease or RA. We here review the current and prospective roles of infliximab in the treatment of autoimmune diseases and other conditions that do not currently have FDA or EMEA approval.     

An assessment of the genetic toxicology of novel boron‐containing therapeutic agents

Boron‐containing compounds are being studied as potential therapeutic agents. As part of the safety assessment of these therapeutic agents, a battery of genetic toxicology studies was conducted. The battery included a bacterial reverse mutation (Ames) assay, an in vitro chromosome aberration assay in peripheral human lymphocytes, and an in vivo rat micronucleus study. The following compounds represent some of the boron‐containing compounds that have been advanced to human clinical trials in various therapeutic areas. The borinic picolinate, AN0128, is an antibacterial compound with anti‐inflammatory activity that has been studied in clinical trials for acne and the treatment of mild to moderate atopic dermatitis. AN2690 (tavaborole) is a benzoxaborole in Phase 3 clinical trials for the topical treatment of onychomycosis, a fungal infection of the toenails and fingernails. Another benzoxaborole derivative, AN2728, a phosphodiesterase‐4 (PDE4) inhibitor, is in Phase 2 clinical trials for the treatment of atopic dermatitis. AN2898, also a PDE4 inhibitor, has been studied in clinical trials for atopic dermatitis and psoriasis. AN3365 is a leucyl‐tRNA synthetase inhibitor that has been in clinical development for the treatment of various Gram‐negative bacterial infections. These five representative compounds were negative in the three genotoxicity assays. Furthermore, AN2690 has been studied in mouse and rat 2‐year bioassays and was not found to have any carcinogenic potential. These results demonstrate that it is possible to design boron‐based therapeutic agents with no genetic toxicology liabilities. Environ. Mol. Mutagen. 54:338–346, 2013. © 2013 Wiley Periodicals, Inc.     

Functional aspects of mammalian neural transplantation

Although initially perceived as a method to study neural development and regeneration, neural transplantation has recently become a very promising approach in its own right as a therapeutic tool to treat neurodegenerative disorders. The development of several animal models which mimic aspects of clinical disorders such as Parkinson's disease, Alzheimer's disease, and Huntington's chorea, provides systems in which to study the potential benefits of grafts derived from different sources. Both fetal and adult donor tissues presently are under investigation. Additionally, cell lines and genetically engineered cells also are being developed as suitable graft material. Important aspects of graft-host interaction, including cell survival, host regeneration, immune interactions, improved behavior, and blood-brain barrier phenomena, may be studied in these transplant models. Advances in this field of biomedical research have led to clinical trials in patients afflicted with Parkinson's disease who now are undergoing transplantation therapy. Thus far, the results have been equivocal, raising important ethical questions about continued clinical studies until more is understood about how neural transplants function and interact with the host. Nevertheless, neural transplantation holds tremendous promise as a future therapeutic tool to treat progressive and irreversible neural disorders.     

TNFα Inhibitors in the Treatment of Psoriasis and Psoriatic Arthritis

Psoriasis is a chronic inflammatory skin disease that can lead to significant physical and psychologic distress for patients. Psoriatic arthritis (PsA), originally thought to be quite a mild disorder, is now recognized as a progressive and destructive arthritis. To date, therapies for both these conditions have been non-specific and unable to maintain long-lasting remission. In addition, many of the current therapies have significant adverse effects, limiting their usefulness. However, elucidation of the pathogenesis of psoriasis and PsA at a molecular level and the development of selective biologic agents have led to an enormous expansion of the armamentarium available to psoriasis patients. Two agents (infliximab and etanercept) selectively block the role of the cytokine tumor necrosis factor (TNF)-alpha and have proved effective in clinical trials in the treatment of both the skin and the joint manifestations of psoriasis. A third anti-TNF alpha agent (adalimumab Humira) is licensed for the treatment of rheumatoid arthritis; however, no studies have been published to date on its use in PsA or psoriasis. It is known that TNF alpha is elevated in both the skin and synovium of psoriatic patients and the effectiveness of its blockade by these two agents in psoriasis and PsA confirms its role in their pathogenesis. Randomized, double-blind, placebo-controlled trials have been performed with both agents in the treatment of psoriasis and PsA; in the case of etanercept these have been to support US FDA approval for use in psoriatic arthropathy. These studies are supported by smaller cohorts in open-label studies and anecdotal reports in the literature. Anti-TNF alpha therapy has proved to have disease-reducing activity in PsA and psoriasis and appears to be well tolerated. These studies have generally featured small numbers of patients and, until a larger cohort of treated patients is available, vigilance must be exercised. A considerable body of post-marketing safety data exists on the use of infliximab in rheumatoid arthritis and Crohn disease and for etanercept in rheumatoid arthritis and PsA. Certain issues, particularly the risk of infection, have emerged as features of the use of these agents. It remains to be seen whether effects seen in other disease entities may be extrapolated to psoriatic patients. More long-term data and experience are needed to define the role of anti-TNF alpha agents in the management of psoriasis and PsA. In particular, more studies are required to elucidate the finer points of co-medication; in some studies both agents have been used with other medications but there have been no formal trials of various possible combinations.     

Current advancements in the treatment of psoriasis: Immunobiologic agents

Psoriasis is a chronic, T-cell mediated autoimmune disorder that affects up to 2.5% of the population worldwide and is accompanied by substantial physical and psychosocial distress. Recent progress in understanding the mechanisms behind the efficacy of conventional treatments has transformed psoriasis from a disease of keratinocyte hyperproliferation to that of T cell pathogenesis. Current treatment options for psoriasis are limited in efficacy and are associated with a number of problems such as inconvenience, organ toxicity, and broad-band immunosuppression. Hence, there has been a demand for new therapeutic approaches that are more convenient, effective, safe, and immunologically selective. Numerous biologic agents that modulate T cell and cytokine action at various steps along the pathogenic sequence have been developed and studied in clinical trials for the treatment of psoriasis. The current review will explore these novel immunomodulatory therapies.     

Gene delivery to the epidermis

Epidermal gene delivery techniques are being developed as an experimental approach to understanding the pathogenesis of skin disorders and for developing therapeutic strategies for the treatment of disease. This technology is being evaluated in many clinical trials in the treatment of disorders such as cutaneous melanoma and skin wounding, with 20% of all gene therapy protocols being applied in the field of dermatology. This review focuses on recent advances in the development of gene transfer technology to the epidermis, describing the diseases that may be amenable to treatment by use of these strategies. We will discuss the advantages and limitations of the currently used techniques and the future prospects for gene therapy via the epidermis.      

Selective Phosphodiesterase Inhibitors for Psoriasis: Focus on Apremilast

Phosphodiesterase (PDE) 4 participates in regulating the inflammatory response by degrading cyclic adenosine 3′,5′-monophosphate (cAMP), a key second messenger. Inhibition of PDE4 increases the intracellular cAMP level, which in turn results in a reduction in inflammatory mediators and an increase in anti-inflammatory mediators. Immune-modulating effects of PDE4 inhibitors have been investigated in a number of inflammatory conditions, such as asthma, atopic dermatitis, chronic obstructive pulmonary disease, Behçet’s disease, psoriasis, and psoriatic arthritis. Apremilast, a selective PDE4 inhibitor, has been shown to block the production of pro-inflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin [IL]-12, IL-17, and IL-23), which are the key players in the pathogenesis of psoriasis. Increased intracellular cAMP levels result in a range of anti-inflammatory effects on numerous cell lines. A decrease in pro-inflammatory activity has been shown to result in a reduced psoriasiform response in preclinical in vivo models of psoriasis, and reduction of biologic activity in a pilot study in humans. The efficacy and safety of apremilast in the treatment of psoriasis have been demonstrated in phase II and III clinical trials. Apremilast demonstrated efficacy in reducing the severity of moderate to severe plaque psoriasis. Treatment with apremilast was well tolerated, with generally mild gastrointestinal complaints, which occurred early in the course of the treatment and resolved over time, and there was no requirement for laboratory test monitoring. These results make apremilast an attractive therapeutic option for plaque psoriasis.     

Therapeutic intervention with inhibitors of co-stimulatory pathways in autoimmune disease

Many humanized antibodies and fusion proteins targeting T-cell co-stimulatory molecules are now in late-stage clinical development (phase II, phase III) or have recently completed phase III clinical trials. Both Amevive, an LFA-3-Ig fusion protein targeting CD2, and Xanelim, a humanized anti-CD11a antibody, have shown efficacy in pivotal phase III trials in patients with plaque psoriasis. These new medicines are poised to enter clinical use in 2002.     

Clinical applications of mesenchymal stromal cell-based therapies for pulmonary diseases: An Update and Concise Review

Lung disorders are a leading cause of morbidity and death worldwide. For many disease conditions, no effective and curative treatment options are available. Mesenchymal stromal cell (MSC)-based therapy is one of the cutting-edge topics in medical research today. It offers a novel and promising therapeutic option for various acute and chronic lung diseases due to its potent and broad-ranging immunomodulatory activities, bacterial clearance, tissue regeneration, and proangiogenic and antifibrotic properties, which rely on both cell-to-cell contact and paracrine mechanisms. This review covers the sources and therapeutic potential of MSCs. In particular, a total of 110 MSC-based clinical applications, either completed clinical trials with safety and early efficacy results reported or ongoing worldwide clinical trials of pulmonary diseases, are systematically summarized following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, including acute/viral pulmonary disease, community-acquired pneumonia (CAP), chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD), interstitial lung diseases (ILD), chronic pulmonary fibrosis, bronchiolitis obliterans syndrome (BOS) and lung cancer. The results of recent clinical studies suggest that MSCs are a promising therapeutic approach for the treatment of lung diseases. Nevertheless, large-scale clinical trials and evaluation of long-term effects are necessary in further studies.     

A new therapeutic for the treatment of moderate-to-severe plaque psoriasis: apremilast

Psoriasis is a common, chronic, inflammatory skin disease. Being a life-long condition, a prolonged and safe control of the disease is needed. Current anti-psoriatic treatments show some limits in terms of tolerability and route of administration. Recently, a new oral small molecule, apremilast, has been approved for the treatment of patients with moderate-to-severe plaque psoriasis. Apremilast is a phosphodiesterase 4 (PDE4) inhibitor that regulates the transduction of intracellular signals, including pro-inflammatory and anti-inflammatory pathways. Because of the favorable safety profile and the oral route of administration, apremilast may represent a promising therapeutic target for moderate-to-severe psoriasis. In this review, we report an updated overview about clinical trials testing apremilast in the treatment of psoriasis and seek to provide comprehensive information about this anti-psoriatic drug and a future perspective of the therapeutic algorithm for psoriasis.     

Cell Adhesion Antagonists

Chronic obstructive pulmonary disease (COPD) and asthma are inflammatory diseases of the lung where a hallmark feature is excessive leukocyte infiltration that leads to tissue injury. Cell adhesion molecules (e.g. selectins and integrins) play a key role in cell trafficking, and in the lung they regulate leukocyte extravasation, migration within the interstitium, cellular activation, and tissue retention. All selectin family members (including L-selectin, P-selectin, and E-selectin) and many of the beta1 and beta2 integrins appear to be important therapeutic targets, as numerous animal studies have demonstrated essential roles for these cell adhesion molecules in lung inflammation. Not surprisingly, these families of adhesion molecules have been under intense investigation by the pharmaceutical industry for the development of novel therapeutics. Integrins are validated drug targets, as drugs that antagonize integrin alphaIIbbeta3 (e.g. abciximab), integrin alphaLbeta2 (efalizumab), and integrin alpha4beta1 (natalizumab) are currently US FDA-approved for acute coronary syndromes, psoriasis, and multiple sclerosis, respectively. However, none has been approved for indications related to asthma or COPD. Here, we provide an overview of roles played by selectins and integrins in lung inflammation. We also describe recent clinical results (both failures and successes) in developing adhesion molecule antagonists, with specific emphasis on those targets that may have potential benefit in asthma and COPD. Early clinical trials using selectin and integrin antagonists have met with limited success. However, recent positive phase II clinical trials with a small-molecule selectin antagonist (bimosiamose) and a small-molecule integrin alpha4beta1 antagonist (valategrast [R411]), have generated enthusiastic anticipation that novel strategies to treat asthma and COPD may be forthcoming.     

Prospects for a T-cell receptor vaccination against myasthenia gravis

T-cell receptor (TCR) vaccination has been proposed as a specific therapy against autoimmune diseases. It is already used in clinical trials, which are supported by pharmaceutical companies for the treatment of multiple sclerosis, rheumatoid arthritis and psoriasis. Current vaccine developments are focusing on enhancement of immunogenicity as well as selecting the best route of immunization and adjuvant to favor the therapeutic effect. In the meantime, academic laboratories are tackling the regulatory mechanisms involved in the beneficial effect of the vaccines to further understand how to control the therapeutic tool. Indeed, several examples in experimental models of autoimmune diseases indicate that any specific therapy may rely on a delicate balance between the pathogenic and regulatory mechanisms. This review presents a critical analysis of the potential of such therapy in myasthenia gravis, a prototype antibody-mediated disease. Indeed, a specific pathogenic T-cell target population and a TCR-specific regulatory mechanism mediated by anti-TCR antibodies and involved in protection from the disease have recently been identified in a patient subgroup. The presence of spontaneous anti-TCR antibodies directed against the pathogenic T-cells that may be boosted by a TCR vaccine provides a rationale for such therapy in myasthenia gravis. The development of this vaccine may well benefit from experience gained in the other autoimmune diseases in which clinical trials are ongoing.     

Th9 cells and IL-9 in autoimmune disorders: Pathogenesis and therapeutic potentials

Naïve CD4⁺ T cells are pleiotropically divided into various T helper (Th) cell subsets, according to their pivotal roles in the regulation of immune responses. The differentiation of Th9 cells, an interleukin (IL)-9 producing subset, can be impacted by specific environmental cues, co-stimulation with transforming growth factor β (TGF-β) and IL-4, and other regulatory factors. Although IL-9 has been recognized as a classical Th2-related cytokine, recent studies have indicated that IL-9-producing cells contribute to a group of autoimmune disorders including systemic lupus erythematosus (SLE), multiple sclerosis (MS), inflammatory bowel diseases (IBD), rheumatoid arthritis (RA) and psoriasis. Studies of Th9 cells in autoimmune diseases, although in their infancy, are expected to be of growing interest in the study of potential mechanisms of cytokine regulatory pathways and autoimmune pathogenesis. Several in vitro and in vivo pre-clinical trials have been conducted to explore potential therapeutic strategies by targeting the IL-9 pathway. Specifically, anti-IL-9 monoclonal antibodies (mAbs) and IL-9 inhibitors may potentially be used for the clinical treatment of allergic diseases, autoimmune diseases or cancers. Here, we review recent research on Th9 cells and IL-9 pertaining to cell differentiation, biological characteristics and pivotal cellular inter-relationships implicated in the development of various diseases.     

Immunomodulatory therapy of eosinophil‐associated gastrointestinal diseases

Eosinophil‐associated gastrointestinal disorders (EGIDs), including eosinophilic esophagitis (EE) and eosinophilic gastroenteritis (EG), are a spectrum of increasingly recognized inflammatory diseases characterized by gastrointestinal symptoms and eosinophilic infiltration of the gastrointestinal tract. Significant morbidity is associated with the development of esophageal strictures in some patients. Immune‐mediated reactions to food allergens appear to drive the inflammation in a subset of patients, especially those with solitary EE, but dietary interventions remain difficult in EE and are less effective in EG. Despite the increasing incidence of these disorders and their increased recognition by physicians, there are currently no medications that either United States or European Union regulatory agencies have specifically approved for use in EGIDs. This lack of safe and effective therapies for EGIDs is a major obstacle in the care of these patients and underscores the need for new therapeutic approaches. This review briefly discusses the currently available ‘off label’ drug treatments for EGIDs, most notably topical and systemic corticosteroids. Pathogenesis studies of EGIDs suggest possible therapeutic targets, and conversely, clinical trials of mechanistically‐targeted therapeutics give insight into disease pathogenesis. Thus, EGID pathogenesis is discussed as an introduction to mechanistically‐targeted immunotherapeutics. The two biologic categories that have been used in EGIDs, anti‐IgE (omalizumab) and anti‐IL‐5 (SCH55700/reslizumab and mepolizumab), are discussed. Because there are similarities in the pathogenesis of EGIDs with asthma and atopic dermatitis, biologic therapeutics currently in early trials for asthma management are also briefly discussed as potential therapeutic agents for EGIDs. Given the deficiencies of current therapeutics and the rapidly advancing knowledge of the pathogenesis of these disorders, EGIDs are an ideal model for translating recent advances in understanding immunopathogenesis into mechanistically‐based therapeutics. Further understanding of the early events in pathogenesis is also needed to develop preventive and disease‐modifying treatments.     

Modulators of androgen and estrogen receptor activity

This review focuses on significant recent findings regarding modulators of androgen and estrogen receptor activity. Selective androgen receptor modulators (SARMs) interact with androgen receptors (ARs), and selective estrogen receptor modulators (SERMs) interact with estrogen receptors (ERs), with variable tissue selectivity. SERMs, which interact with both ERб and ERв in a tissue-specific manner to produce diverse outcomes in multiple tissues, continue to generate significant interest for clinical application. Development of SARMs for clinical application has been slower to date because of potential adverse effects, but these diverse compounds continue to be investigated for use in disorders in which modulation of the AR is important. SARMs have been investigated mostly at the basic and preclinical level to date, with few human clinical trials published. These compounds have been evaluated mostly for application in different stages of prostate cancer to date, but they hold promise for multiple other applications. Publication of the large STAR and RUTH clinical trials demonstrated that the SERMs tamoxifen and raloxifene have interesting similarities and differences in tissues that contain ERs. Lasofoxifene, bazedoxifene, and arzoxifene are newer SERMs that have been demonstrated in clinical trials to more potently increase bone mineral density and lower serum cholesterol values than tamoxifen or raloxifene. Both SARMs and SERMs hold great promise for therapeutic use in multiple disorders in which tissue-specific effects are mediated by their respective receptors.