Compositions comprising sasp modulators and senescence attenuators and uses thereof for modulating cellular senescence

Abstract

Described herein are compositions and methods for modulating cellular senescence of a cell or induction of the senescence-associated secretory phenotype (SASP) in a cell. The methods generally comprise modulating the level or activity of IRE1a as a mean to control cellular senescence and induction of the SASP. Also described are methods for treating and preventing ocular vascular diseases comprising contacting cells in an eye of a subject with a biguanide compound and ophthalmic compositions comprising a biguanide compound.

1 - 2 . (canceled) 
     
     
         3 . A method of inhibiting or preventing (i) senescence of a cell or (ii) the senescence-associated secretory phenotype of a cell in a subject comprising administering to said subject an effective amount of a SEMA3A antagonist. 
     
     
         4 . The method of  claim 3 , wherein said SEMA3A antagonist is (a) a SEMA3A antibody; (b) a SEMA3A antisense or shRNA; and/or (c) a soluble NRP1 polypeptide which binds SEMA3A. 
     
     
         5 . The method of  claim 4 , wherein said SEMA3A antagonist is a soluble NRP1 polypeptide comprising an amino acid sequence having at least 80% identity with the amino acid sequences set forth in SEQ ID NOs: 44, 45, 46, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, or 94. 
     
     
         6 . The method of  claim 3 , wherein said cell is a neuron, a microglial cell, an endothelial cell, a myeloid cell, a monocyte, a macrophage or a fat tissue cell. 
     
     
         7 . The method of  claim 3 , wherein said cell is a terminally differentiated cell. 
     
     
         8 . The method of  claim 3 , wherein said senescence is paracrine senescence. 
     
     
         9 . The method of  claim 3 , wherein said senescence is secondary to cellular ischemia. 
     
     
         10 . The method of  claim 3 , wherein said method reduces IRE1α activation and the expression of Pai1, IL-6, Il-1β, TGF-b, tp53, XBP1(s) and/or VEGF-A in said cells. 
     
     
         11 - 19 . (canceled) 
     
     
         20 . The method of  claim 3 , wherein said cell is from a subject suffering from sarcopenia, neurodegeneration, thinning of the epidermis, skin wrinkling, hair loss, chronic obstructive pulmonary disease (COPD), Idiopathic pulmonary fibrosis (IPF), atherosclerosis, osteoarthritis, osteoporosis, Parkinson's disease, intestinal bowel disease, glaucoma, intervertebral disc degeneration, brain aneurysm, aortic aneurysm, pancreatic fibrosis, cystic fibrosis, obesity, or metabolic syndrome. 
     
     
         21 - 143 . (canceled) 
     
     
         144 . The method of  claim 5 , wherein said soluble NRP1 polypeptide comprises an amino acid sequence having at least 90% identity with the amino acid sequences set forth in SEQ ID NOs: 44, 45, 46, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, or 94. 
     
     
         145 . The method of  claim 144 , wherein said soluble NRP1 polypeptide comprises an amino acid sequence having at least 90% identity with residues 22-424 of SEQ ID NO: 82. 
     
     
         146 . The method of  claim 145 , wherein said soluble NRP1 polypeptide comprises residues 22-424 of SEQ ID NO: 82. 
     
     
         147 . The method of  claim 146 , wherein said soluble NRP1 polypeptide is fused to a fragment crystallizable (Fc) domain. 
     
     
         148 . The method of  claim 147 , wherein said Fc domain is fused to the carboxy-terminal end of said soluble NRP1 polypeptide. 
     
     
         149 . The method of  claim 147 , further comprising a linker between said soluble NRP1 polypeptide and said Fc domain. 
     
     
         150 . The method of  claim 3 , further comprising administering an effective amount of (i) an inhibitor of IRE1α expression; (ii) an inhibitor of IRE1α RNAse activity; (iii) a biguanide compound or (iv) an mTOR inhibitor, to said subject. 
     
     
         151 . The method of  claim 150 , comprising administering an effective amount of a biguanide compound to said subject. 
     
     
         152 . The method of  claim 151 , wherein said biguanide compound is metformin, phenformin, buformin, proguanil, chlorproguanil, Synthalin A, Synthalin B, or any combination thereof. 
     
     
         153 . The method of  claim 152 , wherein said biguanide compound is metformin.