Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-12-27
2004-06-15
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S021800
Reexamination Certificate
active
06750198
ABSTRACT:
The invention relates to a preparation for the treatment of pigmentation disorders of the human and animal body with the use of the protein DCoH and the DNA and/or RNA coding for said protein as the active ingredient.
The enzyme DCoH of the dimerization factor of the HNF-1 homeodomanial proteins (HNF-1∝ and HNF-1&bgr;). DCoH is participating by means of said mechanisms in the control of the gene expression (see D. B. MENDEL ET AL in Science 254 (1991; page 1762). The protein is known at the same time as the ptrin-4∝-carbinolamine-dehydratase PCD and participates in the tetrahydrobiopterin regeneration (see B. A. CITRON ET AL, Proc. Natl. Acad. Sci. USA 89; 1992; page 11891). PCD engages in the process of the biosynthesis of L-tyrosine from L-phenylalanine. In the latter cycle, PCD is tied in together with phenyl-alanine hydroxylase and participates in the regeneration of (6R)5,6,7,8-tetrahydrobiopterin. Independently thereof, however, DCoH/PCD is found also in the vertebral El. and in the pigmented epithelium of the eye, and in the skin and the brain—see E. POGGE V. STRANDMANN and G. U. RYFFEL, Development 121 (1995); page 1217; E. POGGE V. STRANDMANN ET AL in Int. J. Dev. Biol. 42 (1998) page 53).
After the first data on the purification and cloning of DCoH were supplied by D. B. MENDEL ET AL in Science 254 (1991), page 1762, both the peptide sequence and the nucleic acid sequence of human, mouse and rat-DCoH coding for said protein have been described for the first time in U.S. Pat. Nos. 5,403,712 and 5,620,887. Reference is made to said patents with respect to all relevant structural data. DCoH/PCD has been found to be a more or less universal principle in the development of vertebrae, in particular also for their early development. It possesses both catalytic as well as regulating properties and is present in a greater number of types of cells. It is closely associated in some of said cell types with the nuclear transcription factors HNF-1∝ and HNF-1&bgr;, and in other cell types it is tied into the phenylalanine-hydroxylase enzyme complex. The presence of DCoH/PCD in cell types in the absence of HNF-1or phenylalanine-hydroxylase suggests that the protein also cooperates with cellular partners that are different from those cell types.
Vitiligo, for example, is a known pigmentation disorder. Vitiligo is characterized by white, pigment-free, mostly gradually growing patches with a hyperpigmented edge and is attributed to an inhibition of the melanin synthesis. The phenomenon may occur in conjunction with other diseases such as diabetes mellitus. No causal treatment has been possible until now. Vitiligo seems to be associated with an insufficiency of DCoH.
Other pigmentation disorders are, for example forms of canities, i.e. grayness of the hair, both in the physiological form occurring prematurely and at higher age levels. In this instance, too, no causal therapies are known.
A disease that is linked with phenomena of de-pigmentation is alopecia areata, which is a local, suddenly beginning and causally unclear loss of hair, in particular also of the hair of the head. In connection with this type of loss of hair, the hair follicles are preserved, but remissions occur spontaneously in the course of which the affected hair is (first) growing again white. The disease is therefore connected with a pigmentation disorder.
Furthermore, the Usher syndrome and the Waardenburg syndrome are connected with pigmentation disorders. Moreover, numerous disorders are known that are connected with (local) hyperpigmentation.
The effects of the phenomena and diseases mentioned above have been described in great detail; however, it has not been possible to clarify their causes. The assumption that the peptide DCoH/PCD might play a role in this connection has been expressed with respect to vitiligo; however, this has not been proven. Many factors do in fact suggest that the reduction of the enzymatic activity of DCoH observed in connection with mild forms of hyperphenylalaninemia and vitiligo may be a consequence but not the cause of said disorders. It has been proven that an excess supply of the cofactor tetrahydrobioterine required for the formation of L-tyrosine from L-phenylalanine is present in the affected cells.
Overall, there is a need for preparations that are suited for the treatment of pigmentation disorders of the human and animal body and of the phenomena connected with such disorders.
It has now been surprisingly found that DCoH/PCD is suitable for creating de novo pigmented cells. In this process, DCoH is not a link in the melanin synthesis whose absence leads to de-pigmentation, but an “artificial hyper-expression” takes place that triggers the pigmentation. Furthermore, it has been found that DCoH antiserum is suited for weakening pigmentation or for preventing it (its occurrence).
Therefore, the object of the invention is a preparation for the treatment of pigmentation disorders in which a physiologically active amount of the protein DCoH, of the DNA and/or RNA coding for said protein, or of DCoH-antibodies is contained as the active ingredient in a pharmaceutically acceptable excipient.
The preparation as defined by the invention contains the protein DCoH triggering the pigmentation, or as an alternative or supplement the DNA and/or RNA coding for said protein, or as an alternative DCoH-antibodies or antiserum as the active ingredients.
The effect of DCoH/PCD has been demonstrated experimentally after mRNA was injected into oocytene. Since the RNA in the cell is the product of the transcription of the corresponding DNA, and is itself transformed into the protein, the efficiency of all three active ingredients, i.e. of the protein, the DNA and the RNA, is secured, whereby certain spectra may occur with respect to the intensity and duration of the effect. The protein sequence and the nucleic acid sequence of DCoH and of the DNA coding for said protein are described in U.S. Pat. Nos. 5,403,712 and 5,620,887. The preparation of antiserum has been described in Development 121, page 1217 (1995). In detail, both poly- and monoclonal antibodies can be considered for the purpose as defined by the invention.
The preparation as defined by the invention for the treatment of pigmentation disorders contains the active ingredient in a usually employed, pharmaceutically acceptable and compatible excipient. Such excipients are known both for topical and parenteral administration. Possible are, furthermore, gene-therapeutic forms of administration in connection with which the gene decoding for the DCoH is introduced into the target cell. The concentrations of the active ingredient are the same as commonly applied in the field of protein/DNA/RNA therapy and are oriented on the concentrations normally found in the target cells, i.e. such concentrations are at the normal level or higher.
In topical administrations, the preparation can be applied to the skin, whereby the active ingredient is contained in a transdermally effective excipient. Such excipients, which are conceived in the present case in the form of penetration aids or penetration accelerators and present in most cases in the form of liposomes, are known. Furthermore, the preparation may be applied by means of a transdermal system, which is useful particularly in the treatment of local disorders.
In topical applications that are directed at certain regions or cells, for example in connection with hyper-pigmented or de-pigmented regions of the skin or areas of hair growth, especially the application of liposomes developed for that purpose is recommended, such as the liposomes described by R. M. HOFFMAN in the Journal of Drug Targeting, vol. 6 (1997), 67. HOFFMANN describes the hair follicle-selective introduction of macromolecules up to the active gene with a target system based on topically applied liposomes based on phosphatyl choline. The system is applicable to melalins, proteins, genes and the like introduced into liposomes or bonded to the latter.
Cationic lipids for the intracellular dispensing of biologically active
Collard & Roe P.C.
Fumedica GmbH
Witz Jean C.
LandOfFree
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