Compositions and methods for the treatment of aberrant angiogenesis

Abstract

The present subject matter provides compositions, formulations, and methods for inhibiting, treating, or preventing aberrant angiogenesis in a subject.

1 . A method for inhibiting, treating, or preventing aberrant angiogenesis or small vessel diseases (SVDs) in a subject, comprising:
 (a) administering to said subject an effective amount of a Runt-Related Transcription Factor 1 (RUNX1) inhibitor or a PIM3 Proto-Oncogene, Serin/Threonin Kinase (PIM3) inhibitor, or   (b) administering to said subject a NOTCH inhibitor in an amount that is effective to reduce RUNX1 expression or activity, or   (c) (i) increasing the expression of IGFBP3 in said subject: or (ii) administering to said subject an effective amount of IGFBP3, or   (d) altering a RUNX1 or PIM3 gene in said subject.   
     
     
         2 . The method of  claim 1 , wherein the aberrant angiogenesis is aberrant ocular angiogenesis. 
     
     
         3 . The method of  claim 1 , wherein said subject comprises proliferative diabetic retinopathy (PDR), macular edema, non-proliferative diabetic retinopathy, age-related macular degeneration (AMD), ocular neovascularization, ocular ischemic syndrome, retinopathy of prematurity (ROP), a retinal vein occlusion, ocular ischemic syndrome, neovascular glaucoma, a retinal hemangioma, Coates' disease, FEVR, type 1 diabetes, type 2 diabetes, diabetic retinopathy (DR), a hemangioma, neovascular glaucoma, a vascular malformation, a cerebral cavernous malformation, Von Hippel-Linda disease, or Norrie disease. 
     
     
         4 . The method of  claim 1 , wherein said subject comprises a melanoma, a solid tumor, or a cancer other than leukemia. 
     
     
         5 .- 7 . (canceled) 
     
     
         8 . The method of  claim 4 , wherein said solid tumor comprises a dimension that is greater than at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mm or more and/or a volume of at least about 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10 mm 3  or more. 
     
     
         9 . The method of  claim 1 , wherein said RUNX1 inhibitor or said PIM3 inhibitor is administered as part of a treatment regimen that does not comprise an additional antiangiogenic inhibitor. 
     
     
         10 . The method of  claim 9 , wherein said treatment regimen does not comprise a vascular endothelial growth factor (VEGF) pathway inhibitor. 
     
     
         11 . The method of  claim 1 , wherein said RUNX1 inhibitor or said PIM3 inhibitor is administered as a monotherapy. 
     
     
         12 .- 16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein said RUNX1 inhibitor or said PIM3 inhibitor comprises an aptamer, an oligonucleotide, a peptide, an antibody or a fragment thereof, or a small molecule. 
     
     
         18 . The method of  claim 17 , wherein said RUNX1 inhibitor binds to RUNX1 and/or CBFβ. 
     
     
         19 . The method of  claim 17 , wherein said RUNX1 inhibitor binds to RUNX1 or said PIM3 inhibitor binds to PIM3. 
     
     
         20 . The method of  claim 17 , wherein said RUNX1 inhibitor comprises Ro5-3335. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 17 , wherein said oligonucleotide comprises at least about 10, 15, 20, 25, 30, or more nucleotides in a sequence that is complementary to a nucleotide sequence within a gene or mRNA molecule that encodes RUNX1 or PIM3. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 1 , wherein altering said RUNX1 or PIM3 gene comprises the administration of (i) a Cas protein, a zinc finger nuclease (ZFN), or a transcription activator-like effector-based nuclease (TALEN), or (ii) an expression vector encoding a Cas protein, a ZFN, or a TALEN, to said subject. 
     
     
         25 . The method of  claim 1 , wherein said gene is altered with via a CRISPR-Cas9 system. 
     
     
         26 . (canceled) 
     
     
         27 . A composition comprising an effective amount of a RUNX1 inhibitor or a PIM3 inhibitor and an ophthalmically acceptable vehicle. 
     
     
         28 .- 48 . (canceled) 
     
     
         49 . A kit comprising
 (a) (i) an agent for detecting the level of RUNX1; (ii) an agent for detecting the level of PIM3; or (iii) an agent or detecting the level of IGFBP3, and   (b) instructions for using the agent for diagnosing or detecting aberrant angiogenesis, for identifying whether a subject is at risk of developing a disease that comprises aberrant angiogenesis, for determining the progression of the disease, for assessing the efficacy of a treatment for the disease, and/or for adjusting the dose of a compound during the treatment of disease.   
     
     
         50 .- 51 . (canceled) 
     
     
         52 . The method of  claim 1 , wherein the SVD comprises cerebral small vessel disease, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), age-related macular degeneration (AMD), cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), NOTCH3 loss-of-function-associated SVD, Notch 3 hyperactivation-associated SVD, nephropathy, microangiopathy, heart failure, Alagille syndrome, familial tetralogy of Fallot, patent ductus arteriosus, cerebral cavernous malformation, or diabetic retinopathy. 
     
     
         53 .- 55 . (canceled)