Title: Use of strains of parapoxvirus ovis against organ fibrosis
United States Patent: 6,632,647
Issued: October 14, 2003
Inventors: Hirth-Dietrich; Claudia (Wuppertal, DE); Schlapp; Tobias (Cologne, DE); Siegling; Angela (Paris, FR); Knorr; Andreas (Erkrath, DE); Weber; Olaf (Woodbridge, CT); Theiss; Gudrun (Wuppertal, DE)
Assignee: Bayer Aktiengesellschaft (Leverkusen, DE)
Appl. No.: 903005
Filed: July 11, 2001
The present invention relates to the use, in humans, of inactivated parapoxviruses for the prophylaxis and treatment of diseases which are accompanied by an increased deposition of collagen, with it being possible for both internal organs, such as the liver, and the skin and its appended structures, to be affected. The invention relates, in particular, to liver fibrosis and/or liver cirrhosis consequent upon virus hepatitis, or to ethanol-induced liver diseases and to cystic fibrosis.
Description of the Invention
The present invention relates to the use in humans of inactivated parapoxviruses in the prophylaxis and treatment of diseases which are accompanied by increased deposition of collagen, in connection with which both internal organs, such as liver, and the skin and its appended structures can be affected. The invention relates, in particular, to liver fibrosis and liver cirrhosis following viral hepatitis, or ethanol-induced liver diseases, and also cystic fibrosis.
The present invention relates, in particular, to the use in humans of isolates of Parapoxvirus ovis, for example the strains D1701, orf-11, Greek orf strain 176, Greek orf strain 155, New Zealand (NZ) isolates, e.g. NZ2, NZ7 and NZ10, and also Baypamun.RTM., which is derived from D1701.
In addition to the starting strains, the invention also relates to the descendants which are obtained by passaging and/or adaptation to particular cells, for example WI 38. In addition to the complete viruses, the invention also relates to parts or fragments of these viruses. Parts are to be understood as being genomic or subgenomic fragments which are expressed using suitable vectors, for example vaccinia, in suitable systems such as fibroblast cell cultures. Fragments are understood as being the fractions which are obtained by biochemical purification, such as chromatography, or the particles which are obtained after using physical methods, such as disruption by means of sonication.
It is known that Parapoxvirus can stimulate the nonspecific immune reaction in vertebrates. Baypamun.RTM., which is a preparation of chemically inactivated Parapoxvirus ovis, strain D1701, is used for the prophylaxis, metaphylaxis and therapy of infectious diseases and for preventing stress-induced diseases in animals.
While the patent DE 3 504 940 A (Mayr, Anton) teaches the favourable effect of Baypamun.RTM. in conditions such as immunoinsufficiency induced by energy-rich irradiation, chemotherapy, AIDS, immunosuppression, age-associated damage and detoxifying effects, it does not teach the immediate reduction of liver fibrosis. DE 3 504 940 also teaches that Baypamun.RTM. supports the efficacy of a tumour therapy as an adjunct and that it detects newborn children from diseases caused by inadequate maternal immune defence.
Taking the present state of knowledge as the starting point, it has now been found, surprisingly, that administration of inactivated parapoxviruses can reduce or prevent liver fibrosis. In animal models, this effect has been found in the case of carbon tetrachloride-induced liver fibrosis, which is based on toxic liver damage, and in the case of liver fibrosis which is induced by heterologous serum and in which there is no liver inflammation. The extent of the therapeutic effect is also surprising: the excessive production of collagen which is associated with liver fibrosis is inhibited by 60% in the carbon tetrachloride model, while it is almost completely inhibited in the serum model. In agreement with these results from long-term experiments, it was then possible to demonstrate, from acute administration of carbon tetrachloride, that Baypamun.RTM. and the preparation obtained from the abovementioned Parapoxvirus ovis strains inhibit the transformation of the hepatic stellate cells into the collagen-producing myofibroblast type.
While liver fibrosis and/or liver cirrhosis can be induced by different noxas, such as viral infections and alcohol abuse, the different pathomechanisms enter a common final path, i.e. collagen production. As the animal experiment results from the above-described non-infectious models demonstrate, the administration of inactivated parapox viruses surprisingly prevents collagen deposition independently of the inducing noxa.
Parapoxviruses therefore open up a novel therapeutic principle for exerting an effect on the final path which is common to all the diseases leading to fibrosis.
This effect suggests that, when parapoxvirus preparations are used, a particularly effective therapy will be achieved, even in the case of virus-induced liver fibrosis, since it is known that such preparations possess additional immunostimulatory effects.
The powerful antifibrotic effect of Baypamun.RTM. which has now been found opens up the possibility of employing Baypamun.RTM. or preparations of NZ2 as the reference standard for assessing antifibrotic effects in assays for identifying antifibrotic substances.
Inactivated parapoxviruses or their descendants, and preparations obtained from the above strains, consequently possess an all-embracing antifibrotic spectrum of activity and are therefore suitable not only for the prophylaxis and therapy of fibrotic diseases of the liver but also in connection with fibrotic diseases of other organs, for example of the lungs, the pancreas, the heart and the skin. Particular preference is given to using isolates of parapoxviruses in the prophylaxis and treatment of liver fibrosis and liver cirrhosis.
Depending on the clinical problem, the parapoxvirus-based therapeutic agent is administered systemically, that is, for example, intramuscularly, subcutaneously, intraperitoneally, intravenously, orally or by inhalation, or else locally. The parapoxvirus is then present purified and lyophilized, and is suspended in a suitable solvent immediately prior to administration, or is present in another suitable formulation, or is present in a gastric juice-resistant oral administration form or some other oral administration form.
In this connection, several administrations, or long-term treatment in accordance with chronological schemes which correspond to the requirements of the clinical problem, may be necessary.
The present invention relates to the use of isolates of parapoxviruses, which are obtained from the strains D1701, orf-11, Greek orf strain 176, Greek orf strain 155, and the New Zealand (NZ) strains, for producing medicaments which have a preventive or curative effect on organ fibroses in humans. Preference is given to using New Zealand (NZ) strains, i.e. the strains NZ2, NZ7 and NZ10, for producing medicaments which have a preventive or curative effect on organ fibroses in humans, with the strain NZ2 being particularly preferred. In addition to this, the above-described parapoxviruses can be modified by passaging or adaptation to suitable cells, and those parapoxviruses which have been obtained by passaging or adaptation can be used for producing medicaments which have a preventive or curative effect on organ fibroses in humans, in connection with which it is possible to use human cells, such as WI-38, MRC-5, bovine cells, such as BK-K13A47/Reg or MDBK, and ovine cells, such as MDOK, for example, for the passaging or adaptation. It is also possible to use parts or fragments of the abovementioned parapoxviruses for producing medicaments which have a preventive or curative effect on organ fibroses in humans. Parts are understood as being genomic or subgenomic fragments which are expressed in suitable systems, such as fibroblast cell cultures, using suitable vectors, such as vaccinia viruses, and fragments are understood as being the fractions, which are obtained by biochemical purification, such as chromatography, of the viral particles which are expressed or which are physically disrupted, for example by the influence of ultrasonication. The invention furthermore relates to the use of the above-described Parapoxvirus ovis strains, or of the modifications which are obtained therefrom as described above, in combination with other agents for producing medicaments and medicament preparations which have a preventive or curative effect on organ fibroses in humans, and to the use of Baypamun.RTM., on its own or in combination with other agents, for producing medicaments and medicament preparations which have a preventive or curative effect on organ fibroses in humans. The invention preferably relates to the use of the above-described Parapoxvirus ovis strains, or of the modifications which are obtained therefrom as described above, in combination with other agents in a formulation for oral administration, for example in gastric juice-resistant capsules.
The invention furthermore relates to the use of Baypamun.RTM. or preparations of NZ2 as a reference for assessing antifibrotic effects in assays for identifying antifibrotic substances.
Claim 1 of 12 Claims
What is claimed is:
1. A method of treating organ fibroses in humans, comprising administering to a human an effective amount of an isolate of an inactivated parapoxvirus.