Use of telomerase inhibitors for the treatment of myeloproliferative disorders and myeloproliferative neoplasms

Abstract

Provided herein are methods for reducing neoplastic progenitor cell proliferation and alleviating symptoms associated in individuals diagnosed with or thought to have Essential Thrombocythemia (ET). Also provided herein are methods for using telomerase inhibitors for maintaining blood platelet counts at relatively normal ranges in the blood of individuals diagnosed with or suspected of having ET.

1 . A method for alleviating at least one symptom associated with a myeloproliferative neoplasm selected from Essential Thrombocythemia (ET) and Polycythemia vera (PV) in an individual in need thereof, the method comprising: administering a clinically effective amount of a telomerase inhibitor to the individual, wherein administration of the telomerase inhibitor alleviates at least one symptom associated with the myeloproliferative neoplasm. 
     
     
         2 . The method of  claim 1 , wherein the myeloproliferative neoplasm is Essential Thrombocythemia (ET). 
     
     
         3 . The method of  claim 2 , wherein the symptom comprises fatigue, headache, vision disturbances or silent migraines, dizziness or lightheadedness, coldness or blueness of fingers or toes, burning, redness and pain in the hands and feet nosebleeds, bruising, heavy periods, gastrointestinal bleeding, blood in the urine, stroke transient ischemic attack (TIA), heart attack, deep vein thrombosis or pulmonary embolus. 
     
     
         4 . The method of  claim 1 , wherein the myeloproliferative neoplasm is Polycythemia vera (PV). 
     
     
         5 .- 8 . (canceled) 
     
     
         9 . A method for reducing neoplastic progenitor cell proliferation in an individual diagnosed with or suspected of having a myeloproliferative neoplasm selected from Essential Thrombocythemia (ET) and Polycythemia vera (PV), the method comprising: administering a clinically effective amount of a telomerase inhibitor to the individual, wherein administration of the telomerase inhibitor reduces neoplastic progenitor cell proliferation in the individual. 
     
     
         10 . The method of  claim 9 , wherein the myeloproliferative neoplasm is Essential Thrombocythemia (ET). 
     
     
         11 . The method of  claim 9 , wherein the myeloproliferative neoplasm is Polycythemia vera (PV). 
     
     
         12 .- 14 . (canceled) 
     
     
         15 . The method of  claim 9 , wherein reduced neoplastic progenitor cell proliferation results in platelet counts of less than about 600×10 3 /μL in the blood of the individual. 
     
     
         16 . The method of  claim 9 , wherein the individual is resistant or intolerant to a prior non-telomerase inhibitor-based therapy. 
     
     
         17 . A method for maintaining blood platelet counts of between less than about 400×10 3 /μL in the blood of an individual diagnosed with or suspected of having essential thrombocythemia, the method comprising: administering a clinically effective amount of a telomerase inhibitor to the individual, wherein administration of the telomerase inhibitor maintains blood platelet counts of less than about 400×10 3 /μL in the individual. 
     
     
         18 . The method of  claim 17 , wherein the telomerase inhibitor is administered no more than once every two weeks. 
     
     
         19 . A method for reducing bone marrow fibrosis in an individual diagnosed with or suspected of having a myeloproliferative neoplasm selected from Essential Thrombocythemia (ET) and Polycythemia vera (PV), the method comprising: administering a clinically effective amount of a telomerase inhibitor to the individual, wherein administration of the telomerase inhibitor reduces bone marrow fibrosis in the individual. 
     
     
         20 . The method of  claim 9 , wherein the telomerase inhibitor comprises an oligonucleotide. 
     
     
         21 . The method of  claim 20 , wherein the telomerase inhibitor comprises an oligonucleotide with the following characteristics:
 (a) 10-20 bases in length;   (b) complementary to the RNA component of telomerase; and   (c) comprises at least one N3′→P5′ thiophosphoramidate internucleoside linkage.   
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 21 , wherein the oligonucleotide comprises the sequence TAGGGTTAGACAA (SEQ ID NO:12). 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 21 , wherein the oligonucleotide comprises N3′→P5′ thiophosphoramidate internucleoside linkages. 
     
     
         26 . The method of  claim 20 , wherein the oligonucleotide further comprises a lipid moiety linked to the 5′ and/or 3′ end of the oligonucleotide. 
     
     
         27 . The method of  claim 26 , wherein the lipid moiety is linked to the 5′ and/or 3′ end of the oligonucleotide via a linker. 
     
     
         28 . The method of  claim 27 , wherein the linker is a glycerol or aminoglycerol linker. 
     
     
         29 . The method of  claim 27 , wherein the lipid moiety is a palmitoyl (C16) moiety. 
     
     
         30 . The method of  claim 9 , wherein the telomerase inhibitor is imetelstat. 
     
     
         31 . The method of  claim 9 , wherein the telomerase inhibitor is administered with a pharmaceutically acceptable excipient. 
     
     
         32 . The method of  claim 9 , wherein the telomerase inhibitor is formulated for oral, intravenous, subcutaneous, intramuscular, topical, intraperitoneal, intranasal, inhalation, or intraocular administration. 
     
     
         33 . The method of  claim 9 , wherein administration of the therapeutically effective amount of the telomerase inhibitor comprises contacting one or more neoplastic progenitor cells with the telomerase inhibitor. 
     
     
         34 . The method of  claim 30 , wherein the effective amount of a telomerase inhibitor is 7.5 mg/kg to 9.3 mg/kg. 
     
     
         35 . The method of  claim 30 , wherein the effective amount of a telomerase inhibitor is 9.5 mg/kg to 11.7 mg/kg. 
     
     
         36 . The method of  claim 9 , wherein administration of the telomerase inhibitor does not inhibit cytokine-dependent megakaryocyte growth. 
     
     
         37 . The method of  claim 9 , wherein the individual carries a V617F gain of function mutation in the Janus kinase 2 (JAK2) gene. 
     
     
         38 . The method of  claim 37 , wherein administration of the telomerase inhibitor decreases the percentage of JAK2 V617F allelic burden in the individual. 
     
     
         39 . The method of  claim 9 , wherein administration of the telomerase inhibitor inhibits cytokine-independent megakaryocyte growth. 
     
     
         40 . The method of  claim 9 , wherein administration of the telomerase inhibitor inhibits CFU-mega. 
     
     
         41 . The method of  claim 40 , wherein inhibition of CFU-Mega is independent of reduction in JAK2 allelic burden. 
     
     
         42 . The method of  claim 27 , wherein the lipid moiety is linked to the 5′ end of the oligonucleotide via an aminoglycerol linker and a 5′-thiophosphate group. 
     
     
         43 . The method of  claim 1 , wherein the telomerase inhibitor comprises an oligonucleotide. 
     
     
         44 . The method of  claim 1 , wherein the telomerase inhibitor is imetelstat. 
     
     
         45 . The method of  claim 1 , wherein the telomerase inhibitor comprises an oligonucleotide with the following characteristics:
 (a) 10-20 bases in length;   (b) complementary to the RNA component of telomerase; and   (c) comprises at least one N3′→P5′ thiophosphoramidate internucleoside linkage.   
     
     
         46 . The method of  claim 45 , wherein the oligonucleotide comprises N3′→P5′ thiophosphoramidate internucleoside linkages. 
     
     
         47 . The method of  claim 43 , wherein the telomerase inhibitor further comprises a lipid moiety linked to the 5′ and/or 3′ end of the oligonucleotide. 
     
     
         48 . The method of  claim 47 , wherein the lipid moiety is linked to the 5′ and/or 3′ end of the oligonucleotide via a linker. 
     
     
         49 . The method of  claim 48 , wherein the lipid moiety is a palmitoyl (C16) moiety. 
     
     
         50 . The method of  claim 48 , wherein the linker is a glycerol or aminoglycerol linker. 
     
     
         51 . The method of  claim 48 , wherein the lipid moiety is linked to the 5′ end of the oligonucleotide via an aminoglycerol linker and a 5′-thiophosphate group. 
     
     
         52 . The method of  claim 45 , wherein the oligonucleotide comprises the sequence TAGGGTTAGACAA (SEQ ID NO:12).