USE OF SERINE PROTEASE INHIBITORS IN THE TREATMENT OF SKIN DISEASES
This invention relates to therapeutic compounds which are inhibitors of serine proteases, to pharmaceutical compositions thereof and to their use in the treatment of the human or animal body. More specifically, the present invention relates to a method for the treatment, diagnosis or prognosis of skin diseases comprising the administration to a subject in need thereof of a therapeutically effective amount of a Serine protease inhibitor.
1 . A method for treating or preventing a skin disease in a patient comprising the steps of:
(a) providing a recombinant serine protease inhibitor, the inhibitor inhibiting a serine protease, wherein the inhibitor is selected from the group consisting of SEQ ID No 2, SEQ ID No 4, SEQ ID No 6, SEQ ID No 8, SEQ ID No 10, SEQ ID No 12, SEQ ID No 14, SEQ ID No 39, SEQ ID No 40, SEQ ID No 41, SEQ ID No 42, SEQ ID No 43, SEQ ID No 44, SEQ ID No 45, SEQ ID No 46, SEQ ID No 47, SEQ ID No 49, SEQ ID No 50, SEQ ID No 51, SEQ ID No 52, SEQ ID No 53, SEQ ID No 54, SEQ ID No 55, SEQ ID No 56, SEQ ID No 57, SEQ ID No 58 and SEQ ID No 59, or a biologically active fragment thereof having a serine protease inhibitor activity, the biologically active fragment sharing at least 80% amino acids in length with the respective sequence of a substrate active site and exhibiting the same properties as the native sequence from which the inhibitor derives; and
(b) administering a pharmaceutically effective amount of the recombinant serine protease inhibitor to the patient, thereby treating the skin disease.
2 . The method of claim 1 , wherein the serine protease is selected from the group consisting of kallikrein, plasmin, chymotrypsin (Chtr), urokinase (uPA), tryptase and neutrophile elastase (HNE) enzymes and/or a combination thereof.
3 . The method of claim 2 , wherein the kallikrein is selected from the group consisting of human kallikrein 2 (hK2), human kallikrein 3 (hK3), human kallikrein 4 (hK4), human kallikrein 5 (hK5), human kallikrein 6 (hK6), human kallikrein 7 (hK7), human kallikrein 8 (hK8), human kallikrein 9 (hK9), human kallikrein 10 (hK10), human kallikrein 11 (hK11), human kallikrein 12 (hK12), human kallikrein 13 (hK13), human kallikrein 14 (hK14) or human kallikrein 15 (hK15) and/or a combination thereof.
4 . The method of claim 3 , wherein the kallikrein is hK2, hK5, hK7, or hK14 or a combination thereof.
5 . The method of claim 1 , wherein the skin disease is Netherton syndrome, atopic dermatitis, psoriasis or peeling skin syndrome.
6 . A kit for the treatment or prevention of a skin disease comprising a recombinant serine protease inhibitor selected from the group consisting of SEQ ID No 2, SEQ ID No 4, SEQ ID No 6, SEQ ID No 8, SEQ ID No 10, SEQ ID No 12, SEQ ID No 14, SEQ ID No 39, SEQ ID No 40, SEQ ID No 41, SEQ ID No 42, SEQ ID No 43, SEQ ID No 44, SEQ ID No 45, SEQ ID No 46, SEQ ID No 47, SEQ ID No 49, SEQ ID No 50, SEQ ID No 51, SEQ ID No 52, SEQ ID No 53, SEQ ID No 54, SEQ ID No 55, SEQ ID No 56, SEQ ID No 57, SEQ ID No 58 and SEQ ID No 59, or a biologically active fragment thereof having a serine protease inhibitor activity, the biologically active fragment sharing at least 80% amino acids in length with the respective sequence of a substrate active site and exhibiting the same properties as the native sequence from which the inhibitor derives.
7 . A composition comprising a pharmaceutically effective amount of a recombinant serine protease inhibitor, the inhibitor inhibiting a serine protease, wherein the inhibitor is selected from the group consisting of SEQ ID No 2, SEQ ID No 4, SEQ ID No 6, SEQ ID No 8, SEQ ID No 10, SEQ ID No 12, SEQ ID No 14, SEQ ID No 39, SEQ ID No 40, SEQ ID No 41, SEQ ID No 42, SEQ ID No 43, SEQ ID No 44, SEQ ID No 45, SEQ ID No 46, SEQ ID No 47, SEQ ID No 49, SEQ ID No 50, SEQ ID No 51, SEQ ID No 52, SEQ ID No 53, SEQ ID No 54, SEQ ID No 55, SEQ ID No 56, SEQ ID No 57, SEQ ID No 58 and SEQ ID No 59, or a biologically active fragment thereof having a serine protease inhibitor activity, the biologically active fragment sharing at least 80% amino acids in length with the respective sequence of a substrate active site and exhibiting the same properties as the native sequence from which the inhibitor derives.
8 . The composition according to claim 7 , wherein the serine protease is selected from the group consisting of kallikrein, plasmin, chymotrypsin (Chtr), urokinase (uPA), tryptase and neutrophile elastase (HNE) enzymes and/or a combination thereof.
9 . The composition according to claim 8 , wherein the kallikrein is selected from the group consisting of human kallikrein 2 (hK2), human kallikrein 3 (hK3), human kallikrein 4 (hK4), human kallikrein 5 (hK5), human kallikrein 6 (hK6), human kallikrein 7 (hK7), human kallikrein 8 (hK8), human kallikrein 9 (hK9), human kallikrein 10 (hK10), human kallikrein 11 (hK11), human kallikrein 12 (hK12), human kallikrein 13 (hK13), human kallikrein 14 (hK14) or human kallikrein 15 (hK15) and/or a combination thereof.
10 . A method for improving an undesirable skin condition in a patient comprising the steps of:
(a) providing a recombinant serine protease inhibitor selected from the group consisting of SEQ ID No 2, SEQ ID No 4, SEQ ID No 6, SEQ ID No 8, SEQ ID No 10, SEQ ID No 12, SEQ ID No 14, SEQ ID No 39, SEQ ID No 40, SEQ ID No 41, SEQ ID No 42, SEQ ID No 43, SEQ ID No 44, SEQ ID No 45, SEQ ID No 46, SEQ ID No 47, SEQ ID No 49, SEQ ID No 50, SEQ ID No 51, SEQ ID No 52, SEQ ID No 53, SEQ ID No 54, SEQ ID No 55, SEQ ID No 56, SEQ ID No 57, SEQ ID No 58 and SEQ ID No 59, or a biologically active fragment thereof having a serine protease inhibitor activity, the biologically active fragment sharing at least 80% amino acids in length with the respective sequence of a substrate active site and exhibiting the same properties as the native sequence from which the inhibitor derives; and
(b) administering a pharmaceutically effective amount of the recombinant serine protease inhibitor to the patient, thereby improving the undesirable skin condition.
11 . A detection assay for the diagnosis or prognosis of a skin disease in a tissue sample comprising the steps of:
contacting the tissue sample with a recombinant serine protease inhibitor selected from the group consisting of SEQ ID No 2, SEQ ID No 4, SEQ ID No 6, SEQ ID No 8, SEQ ID No 10, SEQ ID No 12, SEQ ID No 14, SEQ ID No 39, SEQ ID No 40, SEQ ID No 41, SEQ ID No 42, SEQ ID No 43, SEQ ID No 44, SEQ ID No 45, SEQ ID No 46, SEQ ID No 47, SEQ ID No 49, SEQ ID No 50, SEQ ID No 51, SEQ ID No 52, SEQ ID No 53, SEQ ID No 54, SEQ ID No 55, SEQ ID No 56, SEQ ID No 57, SEQ ID No 58 and SEQ ID No 59 and having a detected label;
determining and measuring the amount of said detected label; and
correlating this amount to the presence or absence of a skin disease in said tissue sample.