Chronic inflammatory diseases constitute an increasing medical problem area with a high socio-economic impact. These include in particular the following disease groups:                Autoimmune diseases and rheumatic diseases (manifestations on skin, lungs, kidney, vascular system, connective tissue, musculoskeletal system, endocrine system, among other)        Immediate-type allergic reactions and asthma        Chronic obstructive pulmonary diseases (COPD)        Arteriosclerosis        Psoriasis and contact eczema        Chronic rejection reactions after organ or bone marrow transplant        
In the last decades, many of these diseases are showing a rising prevalence, not only in the industrial nations, but partly, worldwide. Thus, in Europe, North America, Japan and Australia, more than 20% of the population already suffers from allergic diseases and asthma. Chronic obstructive pulmonary diseases are currently the fifth most common cause of death worldwide and, according to calculations by WHO, will become the third most common cause of death by the year 2020. Arteriosclerosis, with the secondary diseases myocardial infarction, stroke and peripheral arterial occlusion disease, occupy a leading position in the global morbidity and mortality statistics. Psoriasis and contact eczema are, together with neurodermatitis, the most common chronic inflammatory skin diseases.
The so far only insufficiently understood interactions between environmental factors and genetic disposition result in a subsequent defective regulation of the immune system. Here, the following common principles can be established for these different diseases:
(A) An excessive immune response against antigens, which would normally be harmless for humans, is found. These antigens can be environmental matter (e.g. allergens such as pollen, animal hairs, food, mites, chemical substances such as preservatives, dyes, cleaning products). In these cases, the patients develop an allergic reaction. In the case of, for example, active and passive cigarette smoking, chronic obstructive pulmonary diseases (COPD) occur. On the other hand, the immune system can, however, also react against the components of the own organism, recognize them as foreign and start an inflammatory reaction against them. An autoimmune disease develops in these cases. In all cases, harmless, non-toxic antigens are recognized as foreign or dangerous and an inappropriate inflammatory reaction is started.
(B) The diseases proceed in phases which include initiation, progression, i.e. progressing of the inflammatory reaction, and the associated destruction and alteration with loss in organ functionality (so-called remodelling).
(C) The diseases present patient specific subphenotypic characteristic features.
(D) Components of the innate and acquired immunity are later involved in the initiation, maintenance and in the destruction and alteration processes. Under the influence of the innate immunity (important components: antigen presenting cells with their diverse populations and the complement system), the cells of the adaptive immune system (important components: T- and B-lymphocytes) are activated and differentiated. T-cells take over central functions in the following process by differentiating into highly specialized effectors. In doing so, they activate and acquire certain effector mechanisms, including, in particular, the following functions: Production of antibodies, control of the functionality of effector cells of the immune system (such as, for example, neutrophil, basophil, eosinophil granulocytes), feeding back on functions of the innate immune system, influencing the functionality of non-hematopoietic cells, e.g. epithelium, endothelium, connective tissue, bone and cartilage, and, in particular, neuronal cells. This amounts to a special interaction between immune and nervous system, which has led to the development of the concept of neuro-immunological interaction in chronic inflammations.
Due to the complexity and variety of the disease patterns associated with chronic inflammations, an optimal medicament for the treatment of the diseases must meet the following requirements:
(1) Diseases manifest themselves in patient specific (sub)phenotypes. Medicaments must therefore possess a high patient or case specificity.
(2) Diseases proceed in stages and phases. Medicaments must therefore possess a high stage or phase specificity.
(3) The diseases are regulated by cells of different specialization. Medicaments must therefore cause a cell specific intervention.
(4) The diseases manifest themselves in different organs and compartments. Medicaments must therefore possess a high compartment or organ specificity.
(5) Medicaments must be suitable for a long-term therapy. Immune system reactions against the medicaments must therefore be prevented.
(6) The side effect profile of the medicaments must present an acceptable medical and ethical balance between severity index, prognosis and progress of the disease.
None of the currently available established therapies against chronic inflammations meets these criteria in an optimal way. The treatment with immunoglobulin A is known from DE 695 11 245 T2, and the inhibition of phospholipase A2 (PLA2) and/or coenzyme A-independent transacylase (CoA-IT) is known from DE 695 18 667 T2. For this disease, the currently established therapy concepts are centred on unspecific anti-inflammatory therapy, as well as immune suppression. Many of the applied unspecific anti-inflammatory substances, such as ibuprofen, acetylsalicylic acid and paracetamol, are either not effective enough or are afflicted with a high rate of unwanted side effects. Steroids may have, in contrast, a higher potency, but are themselves afflicted with serious side effects, such as hypertonia, diabetes and osteoporosis. New generation immune suppressing medicaments, such as, for example, cyclosporine and tacrolimus, present hepato- and nephrotoxicity.
This situation has led to the search for and the clinical testing of a plurality of new molecules intended to act more specifically on immunological and cell biological defective regulation. These include cytokines, cytokine receptors and anti-cytokines. Problems related to these new therapeutic applications include a lack of cell and organ specificity, development of unwanted immune reactions against these molecules, and poor effectiveness for different phenotypes.
In recent years, attempts are being made to use a new class of catalytic molecules, the so-called “DNAzymes” (Santoro 1997), as therapeutic agents for inactivating genes, the expression of which is the cause of diseases. DNAzymes are single stranded molecules which can, in principle, bind to complementary areas of the RNA and inactivate it through cleavage. The specific use of DNAzymes as therapeutic agents requires, however, that the genes causing the disease, as well as their RNA, are known in detail. This is so far only the case for few diseases.
The DNAzyme described in WO 01/11023A1 binds RelA (p65) mRNA and is thus directed against the transcription factor NF-κB; WO 00/42173 discloses an EGR-1 mRNA binding DNAzyme. WO99/50452 discloses a 10-23 DNAzyme that can be used in a diagnostic method for detecting nucleic acid mutations. None of the currently known antisense molecules and DNAzymes can be used for producing a medicament for the treatment of chronic inflammations in patients.