Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-03-17
2004-09-14
Ulm, John (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S350000, C530S399000, C424S085100, C424S198100
Reexamination Certificate
active
06790824
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical composition having neurotrophic activity, for treating peripheral and/or CNS-disorders in mammals.
GDF-5 is a bone morpho genetic protein like molecule which, similar to other members of the transforming growth factor beta (TGF-&bgr;) superfamily, has been implicated in neurotrophic functions. For example, TGF-&bgr;1, -&bgr;2, and -&bgr;3, as well as activin A, bone morphogenetic proteins (BMP) -2, -4, -6, -7, -12, glial cell line-derived neurotrophic-like factors (GDNF-like), and GDF-5 have all been shown to promote in vitro the survival of midbrain dopaminergic neurons by various mechanisms. GDNF also acts on a wide spectrum of peripheral neurons.
The discovery of GDNF as a neurotrophic factor for midbrain dopaminergic neurons was a hallmark in the search for novel molecules that may have relevance in the treatment of neurodegenerative diseases, as e.g. Parkinson's disease. The significance of GDNF is further underscored by its efficacy in several animal models of PD including non-human primates, ubiquitous expression in neurons of the CNS, and its widening spectrum of responsive neuron populations. GDNF signals via the tyrosine kinase receptor c-ret in co-operativity with a GPI-linked &agr; receptor, the GDNFR&agr;. GDNF is a member of the TGF-&bgr; superfamily, its closest relatives being neurturin. Targeted mutations of the GDNF or c-Ret genes have indicated that GDNF is essentially required for the development of the kidney, major portions of the enteric nervous system and the sympathetic superior cervical ganglion. However, GDNF does not support the survival of most peripheral neurons in low-density dissociated cultures and defined media. Follow-up experiments in which GDNF has been shown to promote the survival of enriched peripheral autonomic and sensory neurons were all performed using serum throughout the whole culture period. Furthermore, the dopaminotrophic effect of GDNF was established in an extremely complex culture system where its most prominent effect did not become apparent until day 7 in culture.
TGF-&bgr;s are widely distributed and contextually acting cytokines with prominent roles in development and cell cycle control. TGF-&bgr;s have been implicated in the regulation of neuronal survival of e.g. motoneurons, sensory and midbrain dopaminergic neurons. It should be noted, however, that TGF-&bgr; shows no or marginal effects on highly enriched, serum-free neuron cultures, as e.g. sensory neurons.
Thus, the technical problem underlying the present invention is to provide a new system having improved neurotrophic activity, for the treatment of peripheral and/or CNS-disorders in mammals.
The solution to the above technical problem is achieved by the embodiments characterized in the claims.
In particular, the present invention relates to a pharmaceutical composition having a neurotrophic activity, comprising a biologically active amount of at least two cytokines or functionally active derivatives or parts thereof and optionally a pharmaceutically acceptable carrier and/or diluent, wherein at least one of said cytokines is BMP, GDF, TGF-&bgr; or GDNF. The term “BMP” includes BMP-2, BMP4, BMP-6, BMP-7, BMP-11 and BMP-12. The term “TGF-&bgr;” includes TGF-&bgr;1, TGF-&bgr;2 and TGF-&bgr;3. The term “GDNF” includes GDNF, neurturin and persephin. The terms “functionally active derivative” and “functionally active part” refer to a proteinous compound exhibiting at least part of the biological function of the respective cytokine. The cytokines used in the pharmaceutical composition according to the present invention may be selected from the group consisting of GDF such as GDF-5, GDF-6, GDF-7, GDF-8 and GDF-9, GDNF, TGF such as TGF-&bgr; or TGF-&bgr;, e.g. TGF-&bgr;1, TGF-&bgr;2 or TGF-&bgr;3, activin A, BMP such as BMP-2, BMP4, BMP6, BMP-7, BMP-11, BMP-12, BDNF, NGF, neurotrophines such as NT-3 or NT4, EGF, CNTF and FGF such as FGF-2.
Preferred embodiments of the present invention the pharmaceutical composition comprise the following combinations: GDF-5 and NGF or NT-3 or GDNF, TGF-&bgr; and GDNF or FGF-2 or CNTF or NT-3 or NGF, NGF and BMP-4 or BMP-12, NT-3 and BMP-2 or BMP-7 or BMP-12.
As a surprising fact, if at least one of BMP, GDF, TGF-&bgr; and GDNF is present in the above defined pharmaceutical composition, a synergistic effect can be observed resulting in an increased neurotrophic activity, as compared to e. g. known compositions without GDF and/or GNDF.
The pharmaceutical composition according to the present invention may be used for the treatment of peripheral and/or CNS-disorders in mammals, preferably in man, such as Parkinson's disease, Alzheimer's disease, ALS or other dementia, other neurodegenerative disorders of the central nervous system and peripheral neuropathies including diabetes, cisplatinium or other genetic or acquired peripheral nerve diseases.
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Bechtold Rolf
Paulista Michael
Pohl Jens
Unsicker Klaus
Biopharm Gesellschaft zur biotechnologischen Entwicklung von Pha
Chernyshev Olga N.
Hamilton Brook Smith & Reynolds P.C.
Ulm John
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