Use Of Serine Protease Inhibitors In The Treatment Of Neutropenia

Abstract

The 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 of neutropenia comprising the administration to a subject in need thereof of a therapeutically effective amount of a serine protease inhibitor. The invention also comprises prevention of apoptosis of myeloid cells (1) during and after transfection of bone marrow cells performed for gene therapy, (2) during blood stem cell mobilization performed for reconstitution of hematopoiesis and (3) during infusion of cells of the myeloid lineage for reconstitution of hematopoiesis for gene therapy or for treatment of neutropenia by infusion of neutrophils.

1 . A method for the treatment or prevention of patients suffering from neutropenia comprising the administration to said patients in need thereof of a therapeutically effective amount of serine protease inhibitors. 
     
     
         2 . The method of  claim 1 , characterized in that the serine protease inhibitors is a Kallikrein inhibitor. 
     
     
         3 . The method of  claim 2 , characterized in that the Kallikrein inhibitor is selected amongst hK2, hK3, hK4, hK5, hK6, hK7, hK8, hK9 hK10, hK11, hK12, hK13, hK14, hK15 inhibitors or mixtures thereof. 
     
     
         4 . The method of  claim 3 , characterized in that the Kallikrein inhibitor is selected among hK2, hK4, hK11, hK5, hK14 inhibitors or mixtures thereof 
     
     
         5 . The method of  claim 4 , characterized in that the Kallikrein inhibitor is an hK2 inhibitor. 
     
     
         6 . The method of  claim 1 , wherein the serine protease inhibitors are selected from the group comprising SEQ ID N o  2, SEQ ID N o  4, SEQ ID N o  6, SEQ ID N o  8, SEQ ID N o  10, SEQ ID N o  12, SEQ ID N o  14, SEQ ID N o  16, SEQ ID N o  18 or mixtures thereof 
     
     
         7 . Serine protease inhibitors for use in a method of treating or preventing neutropenia in patients which develops due to infections, septicemia, chemotherapy, irradiation, toxic chemicals or as side effects of any medication. 
     
     
         8 . Serine protease inhibitors for use in a method of treating or preventing neutropenia of  claim 7 , wherein the number and/or activation state of neutrophils is impaired. 
     
     
         9 . Serine protease inhibitors of  claim 8 , for use in a method of treating or preventing skin ulcers in diabetes patients in which neutrophils undergo cell death, or skin ulcers developing in patients with peripheral arterial disease associated with hypoxic conditions in the skin and neutrophil dysfunction and apoptosis. 
     
     
         10 . Serine protease inhibitors of  claim 7 , for use in a method of treating or preventing irradiation induced damage of myeloid cells as occurs in the course of treatment of malignancy, accidents in nuclear plants or use of nuclear weapons. 
     
     
         11 . Serine protease inhibitors of  claims 7 - 10 , wherein the serine protease inhibitors is a Kallikrein inhibitor. 
     
     
         12 . Serine protease inhibitors of  claim 11 , characterized in that the Kallikrein inhibitor is selected amongst hK2, hK3, hK4, hK5, hK6, hK7, hK8, hK9 hK10, hK11, hK11, hK12, hK13, hK14, hK15 inhibitors or mixtures thereof 
     
     
         13 . Serine protease inhibitors of  claims 7 - 12 , wherein the serine protease inhibitors are selected from the group comprising SEQ ID N o  2, SEQ ID N o  4, SEQ ID N o  6, SEQ ID N o  8, SEQ ID N o  10, SEQ ID N o  12, SEQ ID N o  14, SEQ ID N o  16, SEQ ID N o  18 or mixtures thereof. 
     
     
         14 . Serine protease inhibitors for use in the in-vitro preparation of neutrophils and their bone marrow precursors
 to perform molecular manipulations for gene therapy prior to infusion of myeloid cells to patients with neutropenia or genetic disorders of the myeloid system,   or to use neutrophils and their bone marrow precursors for infusion to patients with neutropenia or dysfunction of neutrophils.   
     
     
         15 . The serine protease inhibitors of  claim 14 , wherein the serine protease inhibitors are selected from the group comprising SEQ ID N o  2, SEQ ID N o  4, SEQ ID N o  6, SEQ ID N o  8, SEQ ID N o  10, SEQ ID N o  12, SEQ ID N o  14, SEQ ID N o  16, SEQ ID N o  18 or mixtures thereof. 
     
     
         16 . A method for the prevention of apoptosis of myeloid cells of patients, comprising the administration to said patients in need thereof of a therapeutically effective amount of serine protease inhibitors:
 (1) during and after transfection of bone marrow cells performed for gene therapy,   (2) during blood stem cell mobilization performed for reconstitution of hematopoiesis and/or   (3) during infusion of cells of the myeloid lineage for reconstitution of hematopoiesis for gene therapy or for treatment of neutropenia by infusion of neutrophils.   
     
     
         17 . The method of  claim 16 , wherein the serine protease inhibitors are selected from the group comprising SEQ ID N o  2, SEQ ID N o  4, SEQ ID N o  6, SEQ ID N o  8, SEQ ID N o  10, SEQ ID N o  12, SEQ ID N o  14, SEQ ID N o  16, SEQ ID N o  18 or mixtures thereof. 
     
     
         18 . A kit for the diagnosis, prognosis, prophylaxis or treatment of neutropenia in a mammal, characterized in that said kit comprises serine protease inhibitors, optionally with reagents and/or instructions for use. 
     
     
         19 . The kit of  claim 18 , wherein the serine protease inhibitors comprise a detectable label or can bind to a detectable label to form a detectable complex. 
     
     
         20 . The kit of  claims 18 - 19 , wherein the serine protease inhibitors is a Kallikrein inhibitor. 
     
     
         21 . The kit of  claim 20 , wherein in the Kallikrein inhibitor is selected amongst hK2, hK3, hK4, hK5, hK6, hK7, hK8, hK9 hK10, hK11, hK12, hK13, hK14, hK15 inhibitors or mixtures thereof. 
     
     
         22 . The kit of  claims 18 - 21 , wherein the serine protease inhibitors are selected from the group comprising SEQ ID N o  2, SEQ ID N o  4, SEQ ID N o  6, SEQ ID N o  8, SEQ ID N o  10, SEQ ID N o  12, SEQ ID N o  14, SEQ ID N o  16, SEQ ID N o  18 or mixtures thereof.