Recent Patents on Inflammation & Allergy Drug Discovery - Volume 1, Issue 3, 2007

Antisense oligonucleotides represent a novel therapeutic approach for manipulation of gene expression in the treatment of respiratory diseases. This methodology is based on the use of synthetic oligonucleotides to inhibit the expression of a specific target gene by inhibiting the function of the corresponding messenger RNA. Inhaled antisense oligonucleotides are therapeutic alternatives in the treatment of respiratory diseases including allergic asthma; however development of this technology is at an early stage and critical questions related to design, biological activity, and target delivery still remain. The present review will discuss the current status of antisense technology and its application in asthma and allergy. It will be focused in some representative patents including considerations on the future clinical prospects.

A wide range of pathologies are affected by unbalanced cytokine production namely autoimmune, metabolic and infectious diseases. The intrinsic regulation of the pathways involved are very complex, as they include incomplete described intracellular signaling pathways and the pleiotropic cytokine balance within the inflammatory mediators network. Tumor necrosis factor-alpha (TNFα) is considered a key cytokine for the development of diverse pathologies. A wide range of strategies was developed to treat syndromes, including administration of anti-inflammatory cytokines and blockade of main inflammatory molecules such as TNFα. Some intracellular signaling pathways may be common to the regulation of diverse pro-inflammatory components and are also focused as therapeutic target to regulate immune responses. Here, we discuss international bibliography related to unbalanced cytokine mediated disorders and patent literature disclosing methods and products for their treatment.

A significant proportion of bronchial asthma patients have underlying pulmonary fungal infections that contribute to persistent inflammation and allergic reactions. Aspergillus fumigatus is a ubiquitous opportunistic fungal pathogen causing a spectrum of allergic and infectious diseases. Currently, oral corticosteroids form the first line of treatment for allergic aspergillosis and use of antifungals such as itraconazole has been indicated in non-responders. In view of the protective role of innate immunity in host defense against Aspergillus fumigatus, we aimed to identify the relevant innate immune proteins In a series of studies, we identified and established the therapeutic potential of pulmonary collectins SP-A and SP-D and serum collectin MBL in murine models of allergic and invasive aspergillosis. Use of SP-D for diagnosis and therapy of lung disorders and MBL for therapy of various infections including invasive aspergillosis has been patented. Genetic polymorphisms in these genes may result in partial or total loss of function and may increase the host's susceptibility to aspergillosis. Candidate gene association studies showed SNPs in SP-A2 and MBL significantly associate with patients of allergic bronchopulmonary aspergillosis and bronchial asthma with rhinitis. The patients carrying either one or both of GCT and AGG alleles of SP-A2 and patients with A allele at position 1011 of MBL had markedly higher eosinophilia, total IgE antibodies and lower FEV1 (the clinical markers of ABPA). These SNPs may be useful for predicting susceptibility to allergic aspergillosis and bronchial asthma with allergic rhinitis and have been patented. Elucidation of the immunoregulatory role of SP-A, SP-D and MBL in mechanisms of allergy and inflammation suggests that they may also be potentially useful for predisposition diagnosis and therapy of non-fungal bronchial asthma.

Many obstructive airway disorders such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease (COPD) are characterized by mucous metaplasia of the airway epithelium and chronic mucus hypersecretion. Airway occlusion by mucus plugging has been reported in many cases of fatal asthma and conventional mucolytic therapies have been unable to significantly affect mucus-related airway obstruction. Recently, for the first time, direct evidence was presented for improvement of mucus related airway obstruction in a murine model of asthma, highlighting the potential usefulness of therapeutically targeting mucus hypersecretion. We review the emerging targets for inhibition of mucus hypersecretion and discuss some of the recent published scientific literature and patent applications in this field, to provide a framework for further drug discovery in mucus modulation.

Psoriasis is a cutaneous inflammatory disease, which affects 1-5% of general population and can have, particularly in its moderate-severe forms, a significant impact on the quality of life of patients. Although the etiopathogenesis of psoriasis is not yet fully understood, it has been demonstrated that the disease is the result of a complex interaction of genetic, endogenous and environmental factors, where the immune system has a pivotal role. For this reason, the immune system is the main target of many treatments for psoriasis. The most recent evolution in this field are the so-called biologic agents, custom-designed biomolecules obtained by bioengineering. This review summarizes the currently available data about efficacy, safety and undesired effects of five patented biologics officially approved for the treatment of moderate-to-severe psoriasis: adalimumab, alefacept, efalizumab, etanercept and infliximab. Some patent applications concerning possible future evolutions of the above biologics are also discussed.

Multiple sclerosis (MS) is the most common chronic demyelinating disease of the central nervous system, which causes progressive neurological disability. Over the recent decade, there has been an impressive accumulation of data about novel designed immunosuppressive and anti-inflammatory agents promising for treating MS and its animal model, experimental autoimmune encephalomyelitis. Regarding, disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive phase of this disease, novel promising therapeutic strategies could open a light horizon in approaching to an efficient treatment in MS. This review provides a compilation of the more thoroughly studied of these novel immunotherapeutic agents and new aspects of designed molecular targets and patents which have recently evolved.

The pathogenetic aspect of allergic bronchial asthma is characterized by airway inflammation with infiltration of mastcells, basophils, eosinophils, monocytes and T-helper (Th)2 lymphocytes. Most cases of asthma are atopic in nature and aeroallergens such as those released by pollens, Dermatophagoides, moulds etc, act as sensitizer and trigger agents which induce immune response through immunoglobulin E (IgE). IgE is the key mediator of allergic inflammatory reaction and plays a central role in the pathogenesis of atopic-allergic diseases such as those of respiratory tract: rhinitis and bronchial asthma. Currently antiinflammatory and bronchodilation treatments, with integration of other drugs such as antileucotrienes, are effective for most of asthma patients, but there are asthmatic subjects whose disease is incompletely controlled by inhaled or systemic corticosteroids and these patients account for about 50% of the healthcare costs of asthma. A novel therapeutic approach to asthma and other allergic respiratory diseases involves interference in the action of IgE and IgE has been viewed as a target for novel immunological drug development in asthma. Monoclonal antibodies are a molecule able to interact with specific antigens and represent a very interesting options for asthma treatment and their patents. Omalizumab is a humanized recombinant monoclonal anti-IgE antibody developed for the treatment of allergic diseases and with clear efficacy in adolescent and adult patients with moderate-to-severe allergic asthma. This non-anaphylactogen anti-IgE antibody inhibits IgE functions blocking free serum IgE and inhibiting their binding to cellular receptors. By reducing serum IgE levels and IgE receptor expression on inflammatory cells in the context of allergic cascade. Omalizumab therapy is well tolerated and significantly improves symptoms, reducing asthma exacerbations and the need to use high dosage of inhaled corticosteroids to control disease. Moreover, omalizumab improves quality of life of patients with severe persistent allergic asthma that is inadequately controlled by currently available asthma medications. In conclusion omalizumab represents a really new approach to the treatment of atopic asthma and may fulfil an important need in patients with moderate-to-severe asthma.

An alteration of contrast sensitivity (CS) might be connected with structural and functional changes in foveolar and perifoveolar regions caused by different etiologies. We tested the hypothesis, that disturbances of CS can precede the typical changes in macular area in nonproliferative diabetic retinopathy (NPDR) in young patients with diabetes type 1 (T1DM). Material and methods: One hundred and twenty one (121) patients (63 girls and young women and 58 boys and young men) were included in the study; their age ranged 7 to 36 years, (median: 17.6 years). The T1DM duration was 6 to 21 years (median: 9.8 years), and it was diagnosed at the age from 2 to 30 years (median: 10.5 years). CS was examined in all patients repeatedly after one year (range, 11 - 15 months, median: 12.5 months) by means of CSV-1000 instrument in 3, 6, 12, and 18 cycles/degree (c/deg) respectively. In 42 patients older than 18 years of age, the simultaneous CS and fluorescein angiography (FA) were performed; in all of them, the T1DM duration was longer than 10 years. The compensation of the metabolic state was evaluated from average yearlong values of the glycolysated hemoglobin (Hb1Ac). Results: The value of pathologically decreased CS in most of the cases was found in four spatial frequencies and the difference increased depending on the T1DM duration and was from 5 % to 8 % between 6 and 10 years of diabetes duration and from 17 % to 25 % after 15 years of diabetes duration. The total decrease of CS, especially in middle and higher frequencies (6, 12, and 18 c/deg), was determined by the increase of changes at the posterior pole. The early changes at the fundus related to the alteration of CS were of two types: (1) the dilatation of the capillaries with their possible obliteration and tortuosity (DCT) and (2) the changes of the macular structure (CMS) by means of the irregularity of the foveolar reflex and relative retinal thickening without significant macular edema and with increased pigmentation of this region. The combination of these two findings was considered as diabetic preretinopathy (DpR) with preserved visual acuity and decrease of CS in 65 % of cases. The authors also compared the decrease in every single space frequency marked on the CS curvature for NPDR and DpR (distinguished by means of FA). Comparing the NPDR with the norm, the authors found important and fundamental pathological defect of the CS (p = 0.0058). Comparing the DpR with the norm showed significant defect of the CS (p = 0.0197). Comparing NPDR and DpR, the difference was found in more noticeable pathological defect of the CS (p = 0.0228). The T1DM metabolic status during study (actual blood sugar and one year level of Hb1Ac) did not affected the CS positively nor negatively. The regressive study concerning the average Hb1Ac level (norm: 6.5 - 7.5 % by DCCT) during the 10 years' period found, that in NPDR patients the Hb1Ac level was pathologically increased during three quarters (7.5 years) of the follow up period and in DpR patients during one half of the same period (5 years). Conclusions: The CS test by means of the CSV - 1000 device can already detect the first retinal changes in patients with normal visual acuity and is positive in patients with still normal ophthalmologic macular finding.

Asthma is a chronic airway disorder principally characterized by bronchial hyperreactivity and airflow obstruction. Increased epithelial and smooth muscle thickness, goblet cell hyperplasia, increased mucus secretion, abnormal deposition of extracellular matrix (ECM) components in the basement membrane (BM) layer and angiogenesis are all events which occur in asthma and are defined with the general term of remodeling. This is an important feature whose repetition and regeneration may bring to an abnormal or exaggerated response to airway insults. One of the characteristic aspects of asthma is an alteration in structural cell function. Airway smooth muscle cells (ASM), myofibroblasts and fibroblasts have the ability to secrete immunomodulatory cytokines and chemokines and to express cell surface receptors. These elements are all important for cell adhesion and leukocyte activation and may be integral components of the inflammatory response as well. In particular cells such as fibroblasts and myofibroblasts, important regulators in the development and maintenance of allergic airway inflammation, have been studied in depth by our group and several studies regarding their role in asthma therapy have been analyzed.

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