Compositions and methods for treatment of bleeding disorders

Abstract

The present disclosure relates to treatment of bleeding disorders, in particular, hemophilia A (mild, moderate or severe hemophilia) and von Willebrand disease (VWD), Type 1 or Type 2 or Type 3, using VWF targeting agents such as a PEGylated anti-VWF aptamer, BT200.

1 . A method for treating a hereditary bleeding disorder in a subject comprising administering to the subject a therapeutic effective amount of a pharmaceutic composition comprising a VWF targeting agent. 
     
     
         2 . The method of  claim 1 , wherein the hereditary bleeding disorder is an acquired platelet function defect, congenital platelet function defects, disseminated intravascular coagulation (DIC), prothrombin deficiency, fibrinogen deficiency, FV deficiency, FVII deficiency, FX deficiency, FXI deficiency (hemophilia C), FXIII deficiency, combined FV and FVIII deficiency (F5F8D), VKCFD, Glanzmann thrombasthenia, hemophilia A, hemophilia B, immune thrombocytopenic purpura (ITP), von Willebrand disease (VWD) Type 1, von Willebrand disease (VWD) Type 2, and Von Willebrand disease (VWD) Type 3. 
     
     
         3 . The method of  claim 2 , wherein the hereditary bleeding disorder is hemophilia A, VWD Type 1, VWD Type 2, or VWD Type 3. 
     
     
         4 . The method of  claim 3 , wherein the hereditary bleeding disorder is hemophilia A, mild hemophilia, moderate hemophilia, or severe hemophilia. 
     
     
         5 . The method of  claim 3 , wherein the hereditary bleeding disorder is VWD Type 1, VWD Type 1 Vicenza subtype, VWD Type 2a, VWD Type 2b, VWD Type 2b with thrombocytopenia, VWD Type 2m, VWD Type 2n, or VWD Type 3. 
     
     
         6 . The method of any one of  claims 1 - 5 , wherein the VWF targeting agent is a VWF binding agent selected from the group consisting of an antibody, a nanobody, a peptide, an oligonucleotide, a siRNA, a microRNA, a synthetic polynucleotide, and a small molecule. 
     
     
         7 . The method of  claim 6 , wherein the VWF binding agent is a synthetic polynucleotide selected from the group consisting of SEQ ID No.: 3, BT99 (SEQ ID No.: 4), BT100 (SEQ ID No.: 5), BT200 (SEQ ID No.: 6), ARC15105 (SEQ ID No.: 7), and ARC1779 (SEQ ID No.: 8) and variants thereof. 
     
     
         8 . The method of  claim 7 , wherein the VWF binding agent is BT200 (SEQ ID No.: 6) or a variant thereof. 
     
     
         9 . The method of  claim 8 , wherein BT200 increases the levels and activity of VWF, the levels and activity of FVIII, and/or the platelet counts in the blood. 
     
     
         10 . The method of  claim 8 , wherein BT200 is administered to the subject at a dose ranging from 0.1 mg to 48.0 mg, or from 0.1 mg to 20.0 mg, or from 1.0 mg to 10 mg. 
     
     
         11 . The method of  claim 10 , wherein BT200 is administered to the subject at a dose ranging from 0.6 mg to 6.0 mg. 
     
     
         12 . The method of  claim 8 , wherein the VWF binding agent is administered to the subject via subcutaneous injection. 
     
     
         13 . The method of  claim 12 , wherein the VWF binding agent is administered to the subject with multiple doses, and wherein each dose is administered once every other day, or once every three days, or once every five days, or once a week, or once every other week. 
     
     
         14 . The method of any one of  claims 1 - 13 , wherein the treatment of the hereditary bleeding disorder is a therapy treatment or a prophylactic treatment. 
     
     
         15 . The method of  claim 3 , wherein the VWF targeting agent is administered in combination with coagulation factor substitute treatment; the coagulation factor substitute is plasma derived FVIII/VWF concentrates, recombinant FVIII preparations, or recombinant VWF preparations. 
     
     
         16 . A method for preventing a chronic bleeding condition, and/or spontaneous bleeding in a subject comprising administering to the subject a therapeutic effective amount of a pharmaceutic composition comprising a VWF targeting agent. 
     
     
         17 . The method of  claim 16 , wherein the VWF targeting agent is a VWF binding agent selected from the group consisting of an antibody, a nanobody, a peptide, an oligonucleotide, a siRNA, a microRNA, a synthetic polynucleotide, and a small molecule. 
     
     
         18 . The method of  claim 17 , wherein the VWF binding agent is a synthetic polynucleotide comprising PEGylated nucleic acids. 
     
     
         19 . The method of  claim 18 , wherein the VWF binding agent is BT200 (SEQ ID No.: 6), or a variant thereof. 
     
     
         20 . The method of  claim 19 , wherein BT200 is administered at a dose ranging from 1.0 mg to 10.0 mg, or alternatively at a dose ranging from 1.0 mg to 6.0 mg. 
     
     
         21 . A method for blocking VWF clearance in the blood comprising providing an effective amount of a VWF targeting agent that is a synthetic polynucleotide comprising a PEGylation moiety. 
     
     
         22 . The method of  claim 21 , wherein the VWF targeting agent is BT200 (SEQ ID No.: 6), or a variant thereof. 
     
     
         23 . The method of  claim 22 , wherein BT200 is provided at an amount ranging from 0.6 mg to 6.0 mg, or from 1.0 mg to 6.0 mg, or from 1.0 mg to 10.0 mg. 
     
     
         24 . The method of  claim 23 , wherein BT200 increases VWF levels in the blood. 
     
     
         25 . A method for elevating the FVIII levels in the blood of a subject comprising administering to the subject an efficient amount of a composition comprising a VWF targeting agent that is a synthetic polynucleotide comprising a PEGylation moiety. 
     
     
         26 . The method of  claim 25 , wherein the subject is diagnosed with hemophilia A, VWD Type 1, VWD Type 2, or VWD Type 3. 
     
     
         27 . The method of  claim 26 , wherein the VWF targeting agent is BT200 (SEQ ID No.: 6). 
     
     
         28 . The method of  claim 27 , wherein BT200 increases FVIII clotting activity. 
     
     
         29 . A method for increasing platelet counts in the blood of a patient comprising administering to the patient an efficient amount of a composition comprising BT200 (SEQ ID No.: 6), wherein the patient has a low platelet count (thrombocytopenia). 
     
     
         30 . The method of  claim 29 , wherein the thrombocytopenia is associated with a genetic disorder that causes a low platelet count, an enlarged spleen that holds abnormal platelets, a side reaction to a medicine, an autoimmune disease, or a viral infection. 
     
     
         31 . The method of  claim 30 , wherein the disorder is VWD Type 2a, VWD Type 2b with thrombocytopenia, VWD Type 2b, VWD Type 2m, or VWD Type 2n. 
     
     
         32 . A method for treating a hereditary bleeding disorder in a patient with a pharmaceutical composition comprising a VWF binding agent, BT200, comprising:
 a) assessing the hereditary bleeding disorder of said patient and the baseline coagulation function in said patient;   b) determining the optimal dose of BT200 with the assessment of step a) for initial treatment; and   c) providing a weekly dose of BT200 after one-week treatment with the initial dose of BT200 in said patient.   
     
     
         33 . The method of  claim 32 , wherein the hereditary bleeding disorder may be hemophilia A, severe hemophilia, VWD Type 1, VWD Type 2a, VWD Type 2b, VWD Type 2m, VWD Type 2n, or VWD Type 3. 
     
     
         34 . The method of  claim 33 , wherein the assessment includes FVIII activity, VWF antigen levels and/or platelet counts in the blood. 
     
     
         35 . The method of  claim 33 , wherein the patient is treated with a coagulation factor substitute.