Use of therapeutic agents

Abstract

The specification relates to the use of Mcl-1 inhibitors to promote apoptosis in vascular endothelial cells undergoing neovascularisation in disease states.

1 . A method of reducing ocular neovascularization in a subject, the method comprising administering to a subject in need thereof an agent that suppresses Mcl-1 expression or Mcl-1 polypeptide activity and wherein the agent thereby reduces the number of angiogenic vascular endothelial cells while substantially sparing quiescent vascular endothelial cells in the eye. 
     
     
         2 . The method of  claim 1 , wherein the ocular neovascularization is associated with or wherein the subject has been diagnosed with a disease of the eye selected from diabetic retinopathy, pathologic choroidal or retinal neovascularization, age-related macular degeneration, retinopathy of prematurity, ocular trauma or ocular ischemia, surgery induced edema or neovascularization, retinal vein occlusion, Coat's disease, sickle cell retinopathy and neovascular glaucoma. 
     
     
         3 . The method of  claim 1 , wherein the agent binds to Mcl-1 polypeptide and suppresses Mcl-1 polypeptide activity or wherein the agent binds to Mcl-1 nucleic acid and suppresses Mcl-1 polypeptide expression. 
     
     
         4 . The method of  claim 3 , wherein the agent comprises a small inhibitory molecule, or a peptide, or polypeptide. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 3 , wherein the agent comprises or encodes an antisense, siRNA, shRNA, miRNA, ribozyme, DNAzyme or other nucleic acid molecule. 
     
     
         7 . The method of  claim 1 , wherein the agent is in the form of a pharmaceutical or physiological composition suitable for topical or ocular administration of the agent to the eye region. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the subject is a human. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . An agent that suppresses Mcl-1 expression or Mcl-1 polypeptide activity for use in treating a disease or condition of the mammalian eye associated with pathological neovascularization wherein the agent reduces the number of angiogenic endothelial cells in the eye while substantially sparing quiescent endothelial cells in the eye. 
     
     
         21 . The agent of  claim 20  for use, wherein the agent is a membrane-penetrating small molecule inhibitor, peptide, polypeptide or nucleic acid molecule. 
     
     
         22 . The method of  claim 1  or the agent of  claim 20  wherein the agent is active in endothelial cells and completely suppresses Mcl-1 expression or activity therein. 
     
     
         23 . A method of reducing neovascularization in a subject, the method comprising administering to a subject in need thereof an agent that suppresses Mcl-1 expression or Mcl-1 polypeptide activity and wherein the agent thereby reduces the number of angiogenic vascular endothelial cells while substantially sparing quiescent endothelial cells in the tissue. 
     
     
         24 . The method of  claim 23 , wherein the neovascularization is associated with a vascular malformation disorder. 
     
     
         25 . A method of selectively reducing the number of angiogenic endothelial cells while substantially sparing quiescent endothelial cells in a subject, the method comprising administering to the subject an agent that suppresses Mcl-1 expression or Mcl-1 polypeptide activity. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 25  wherein the agent is administered for a time and under conditions effective to reduce the formation of new blood vessels (reduce vascular density) in a tissue or organ of a subject. 
     
     
         28 . The method of  claim 23  or  25 , wherein subject is diagnosed with a tumour of endothelial cell origin. 
     
     
         29 . The method of  claim 28 , wherein the tumour is selected from the group consists of capillary hemangioma, synovial hemangioma, venous hemangioma, arteriovenous hemangioma, epithelioid hemangioma, Kaposiform hemangioendothelioma, retiform hemangioendothelioma, papillary intralymphatic angioendothelioma, composite angioendothelioma, pseudomyogenic (epithelioid sarcoma-like) angioendothelioma, Kaposi sarcoma, epithelioid hemangioendothelioma, and angiosarcoma. 
     
     
         30 . The method of  claim 23  or  25 , wherein the agent binds to Mcl-1 polypeptide and suppresses Mcl-1 polypeptide activity or wherein the agent binds to Mcl-1 nucleic acid and suppresses Mcl-1 expression. 
     
     
         31 . The method of  claim 30 , wherein the agent comprises a small inhibitory molecule, or peptide or polypeptide. 
     
     
         32 . (canceled) 
     
     
         33 . The method of  claim 30 , wherein the agent comprises or encodes an antisense, siRNA, shRNA, miRNA, ribozyme, DNAzyme or other nucleic acid molecule. 
     
     
         34 . The method of  claim 23  or  25 , wherein the agent is in the form of a pharmaceutical or physiological composition. 
     
     
         35 . The method of  claim 23  or  25  or the agent of  claim 20 , wherein the agent completely suppresses Mcl-1 expression or activity in endothelial cells. 
     
     
         36 . The method of  claim 1 ,  23  or  25  or the agent of  claim 20 , wherein apoptosis is increased in venous and sprouting regions comprising proliferating (angiogenic) vascular endothelial cells. 
     
     
         37 . The method of  claim 1 ,  23  or  25  or the agent of  claim 20  wherein apoptosis is not substantially increased in non-angiogenic vascular endothelial cells (spared cells).