Cell-specific active compounds regulated by the cell cycle

Details Cell-specific active compounds regulated by the cell cycle Cell-specific active compounds regulated by the cell cycle

1997-04-25

2002-05-07

Clark, Deborah J. R. (Department: 1632)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C424S093100, C424S093200, C424S093600, C435S320100, C536S023500, C536S024100

Reexamination Certificate

active

06384202

ABSTRACT:

TECHNICAL FIELD
A DNA sequence is described for the gene therapy of diseases associated with the immune system.
In its essential elements, the DNA sequence is composed of an activator sequence, a promoter module and a gene for the active substance.
The activator sequence is activated in a cell-specific or virus-specific manner and this activation is regulated by the promoter module in a cell cycle-specific manner. The choice of activator sequence and active substance depends on the indication area. The DNA sequence is inserted into a viral or non-viral vector, which vector is supplemented with a ligand having affinity for the target cell.
Depending on the choice of activator sequence and active substance, the following can be treated by administering the DNA sequence:
defective formation of blood cells
autoimmune diseases and allergies and, in addition, rejection reactions against transplanted organs
chronic arthritis
viral and parasitic infections and, in addition, prophylaxis of viral, bacterial and parasitic infections, and
leukemias.
A defective immune system causes an extremely wide variety of diseases. These include, for example,
allergies, autoimmune diseases and chronic inflammations, in particular chronic arthritis, due to erroneous functioning of the immune system
rejection of transplanted organs due to the immune system not being adequately inhibited
poor vaccination results and chronic infections, for example by viruses, as a consequence of immune deficiency
leukemias and lymphomas as tumorous degeneration of the immune system.
As is well known, the current therapeutic possibilities for diseases of this nature are inadequate. This will be illustrated using a few examples.
1) Therapy with Cytokines
By now, a substantial number of cytokines and growth factors have become known which are involved in the differentiation, multiplication, maturation and functioning of cells.
For example, the hematopoietic system is controlled by a hierarchy of different cytokines, which ensure, by means of their differing functions, the multiplication of the individual differentiation stages and, over and above the individual differentiation stages, the ongoing formation of mature blood cells such as erythrocytes, thrombocytes, granulocytes, macrophages and lymphocytes (Dexter et al., Haematopoietic Growth Factors, Gardiner Well Communication, Macclesfield (1993)).
In addition, it is known that cytokines and growth factors play an important role in the cooperation of cells with each other (Pusztal et al., J. Pathol. 169, 191 (1993), Cross et al., Cell 64, 271 (1991)).
Thus, in immune resistance, for example, the collaboration between antigen-presenting cells, T lymphocytes and B lymphocytes is controlled by different cytokines with the sequence and concentration of the cytokines being crucial for the nature and strength of the immune reaction (Aulitzky et al., Drugs 48, 667 (1994), Sedlacek et al., Immune Reactions, Springer Verlag (1995)). In addition, resistance to infectious agents, such as viruses, is both influenced and supported by cytokines such as interferons (Edgington, Biotechnol. 11, 465 (1993)).
Knowledge of these relationships has already led to the development of cytokines for the therapy of human diseases, for example of
erythropoietin for curing anemia
G-CSF for curing neutropenia
GM-CSF for curing leukopenia
IL-2 for immune resistance to selected tumors
IFN&agr; for the therapy of chronic viral hepatitis
IFN&bgr; for the therapy of multiple sclerosis
Further cytokines are currently being tested (Aulitzky et al., Drugs 48, 667 (1994)). These include, for example
thrombopoietin for curing thrombocytopenia (Metcalf, Nature 369, 519 (1994))
IL-3 for tumor therapy (de Vries et al., Stem Cells 11, 72 (1993) and for providing support in curing cytopenic conditions of the hematopoietic system (Freudl, Int. J. Immunopharm. 14, 421 (1992))
IL-4 for tumor therapy (Manate et al., Blood 83, 1731 (1994))
IL-6 for curing cytopenic conditions of the hematopoietic system (Brack et al., Int. J. Clin. Lab. Res. 22, 143 (1992))
IL-10 for immunosuppression (Benjamin et al., Leuk. Lymph. 12, 205 (1994))
IL-11 for curing thrombocytopenia (Kobayashi et al., Blood 4, 889 (1993)) IL-12 for tumor therapy (Tahara et al., Cancer Res. 54, 182 (1994))
TNF&agr; for tumor therapy (Porter, Tibitech 9, 158 (1991)).
A common feature of therapy with all cytokines is the disadvantage that they usually have to be administered parenterally every day over a relatively long period of time and, furthermore, that, for their greatest possible efficacy, several cytokines either have to be injected one after the other in the necessary hierarchical sequence or corresponding cytokines have to be present in adequate concentration in the body.
That which is crucial for the effect is the concentration of the particular cytokines at the site of the cell which is to be stimulated. For the sake of simplicity, the cytokines are injected daily either subcutaneously or i.m. While this mode of administration guarantees a delayed systemic distribution, which is what is sought-after, relatively high quantities have to be administered in order to ensure an adequate local concentration at the site of the desired effect. The increased dose which is consequently required constitutes, due to the high level of expenditure involved in producing cytokines, a substantial cost factor which considerably restricts the use of cytokines.
Over and above this, some cytokines give rise, in the therapeutic dose range, to substantial side effects. IL-1 (Smith et al., New Engl. J. Med. 328, 756 (1993)), IL-3 (Kurzrock et al., J. Clin. Oncol. 9, 1241 (1991)) and I1-2 (Siegel et al., J. Clin. Oncol. 9, 694 (1991)) are examples of such cytokines.
Consequently, there is a substantial requirement for novel methods for making cytokines or combinations of cytokines available over a relatively long period of time, and in adequate concentration, at their site of action.
2) Chronic Arthritis
Despite improved antiinflammatory and immunosuppressive medicaments, chronic arthritis is a disease for which only inadequate therapeutic measures are available and which substantially reduces the quality of life and can even shorten life expectancy (Pincus et al., Bull. Rheum. Dis. 41, 1 (1992)). Because of its frequency (approx. 10% of the population of the western world suffers from arthritis) arthritis constitutes a substantial cost factor for national economies.
In view of the fact that medicinal therapy is inadequate, surgical removal of the synovial membranes of the joint capsule (synovectomy) or surgical replacement of the joint is the last possible form of therapy for many patients.
In view of these medicinal and economic problems, chronic arthritis represents a challenge for pharmaceutical research.
However, it can already be predicted today that, irrespective of their nature, medicaments which are administered orally or parenterally will have difficulty in reaching the region of joint inflammation in adequate concentration since they have to diffuse through the synovial capillaries and then passively through the synovial membrane into the joint cavity and from there into the cells lining the joint (Evans et al., Gene Therapeutics, J. Wolff, Editor, page 320, Birkhäuser, Boston 1994).
This diffusion is additionally made more difficult by the fact that the vascularization of the synovial membrane is significantly reduced in rheumatoid arthritis, for example (Stevens et al., Arthritis Rheum. 34, 1508 (1991)). While intraarticular injection of medicaments circumvents the problem of diffusion, the dwell time of the medicament in the joint is so short, owing to the high reabsorption rate, that repeated intraarticular injections over a relatively long period of time are required. These injections are in turn associated with the considerable risk of a joint infection. In addition, they can give rise to substantial side effects on account of the high local concentration of the medicament which is required.
In order to remedy these problems, the systemic or local, intraa

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