Use of engineered viruses to specifically kill senescent cells

Abstract

Polypeptides, viruses, methods and compositions provided herein are useful for the selective elimination of senescent cells. Method aspects include methods for inducing apoptosis in a senescent cell comprising administering to the cell a polynucleotide, virus, host cell, or pharmaceutical composition described herein. Other methods include expressing a pro-apoptotic gene in a senescent cell comprising administering to the cell the polynucleotide, virus, or pharmaceutical composition as described herein.

What is claimed is: 
     
         1 . A polynucleotide comprising a pro-apoptotic gene and a p16 promoter, wherein the expression of the pro-apoptotic gene is regulated by the p16 promoter or an equivalent thereof. 
     
     
         2 . The polynucleotide of  claim 1 , wherein the pro-apoptotic gene is of the group: a caspase, Bik, Puma, Bim, Bax, Bak, Bid, Bad, Bmf, Noxa, and Hrk. 
     
     
         3 . The polynucleotide of  claim 2 , wherein the pro-apoptotic gene is a caspase. 
     
     
         4 . The polynucleotide of  claim 3  wherein the caspase is caspase 8. 
     
     
         5 . The polynucleotide of any one of  claims 1 - 4 , wherein the p16 promoter comprises the human p16 promoter, an equivalent thereof, or a polynucleotide having at least 80% identity to the human p16 promoter. 
     
     
         6 . The polynucleotide of  claim 5 , wherein the p16 promoter comprises a polynucleotide having at least 90% identity to the human p16 promoter. 
     
     
         7 . The polynucleotide of  claim 6 , wherein the p16 promoter comprises a polynucleotide having at least 95% identity to the human p16 promoter. 
     
     
         8 . The polynucleotide of any one of  claims 5 - 7 , wherein the human p16 promoter comprises a sequence corresponding to SEQ ID NO: 1. 
     
     
         9 . The polynucleotide of any one of  claims 1 - 4 , wherein the p16 promoter comprises the mouse p16 promoter, an equivalent thereof, or a polynucleotide having at least 80% identity to the human p16 promoter. 
     
     
         10 . The polynucleotide of  claim 9 , wherein the p16 promoter comprises a polynucleotide having at least 90% identity to the mouse p16 promoter. 
     
     
         11 . The polynucleotide of  claim 10 , wherein the p16 promoter comprises a polynucleotide having at least 95% identity to the mouse p16 promoter. 
     
     
         12 . The polynucleotide of any one of  claims 9 - 11 , wherein the mouse p16 promoter comprises a sequence corresponding to SEQ ID NO: 2. 
     
     
         13 . A viral vector comprising the polynucleotide of any one of  claims 1 - 12 . 
     
     
         14 . The viral vector of  claim 13 , wherein the viral vector is derived from a retrovirus. 
     
     
         15 . The viral vector of  claim 14  wherein the viral vector is derived from a lentivirus. 
     
     
         16 . A pseudotyped viral particle comprising the viral vector of any one of  claims 13 - 15 . 
     
     
         17 . The pseudotyped viral particle of  claim 16 , wherein the viral particle is lytic. 
     
     
         18 . The pseudotyped viral particle of  claim 16  or  17 , wherein the viral particle is capable of infecting non-dividing cells. 
     
     
         19 . A pharmaceutical composition comprising the polynucleotide of any one of  claims 1 - 12 , the viral vector of any one of  claims 13 - 15 , or the pseudotyped viral particle of any one of  claims 16 - 18  and a carrier. 
     
     
         20 . A host cell comprising the polynucleotide of any one of  claims 1 - 12 , the viral vector of any one of  claims 13 - 15 , or the viral particle of any one of  claims 16 - 18 . 
     
     
         21 . A conditionally replicating viral construct comprising an essential viral gene regulated by one or more promoters wherein at least one promoter is the p16 promoter or an equivalent thereof. 
     
     
         22 . The conditionally replicating viral particle of  claim 21  wherein the one or more promoters comprises a chemically inducible promoter. 
     
     
         23 . The conditionally replicating viral particle of  claim 21  or  22 , wherein the p16 promoter comprises the human p16 promoter, an equivalent thereof, or a polynucleotide having at least 80% identity to the human p16 promoter. 
     
     
         24 . The conditionally replicating viral particle of  claim 23 , wherein the p16 promoter comprises a polynucleotide having at least 90% identity to the human p16 promoter. 
     
     
         25 . The conditionally replicating viral particle of  claim 24 , wherein the p16 promoter comprises a polynucleotide having at least 95% identity to the human p16 promoter. 
     
     
         26 . The conditionally replicating viral particle of any one of  claims 23 - 25 , wherein the human p16 promoter comprises a sequence corresponding to SEQ ID NO: 1. 
     
     
         27 . The conditionally replicating viral particle of  claim 21  or  22 , wherein the p16 promoter comprises the mouse p16 promoter, an equivalent thereof, or a polynucleotide having at least 80% identity to the mouse p16 promoter. 
     
     
         28 . The conditionally replicating viral particle of  claim 27 , wherein the p16 promoter comprises a polynucleotide having at least 90% identity to the mouse p16 promoter. 
     
     
         29 . The conditionally replicating viral particle of  claim 28 , wherein the p16 promoter comprises a polynucleotide having at least 95% identity to the mouse p16 promoter. 
     
     
         30 . The conditionally replicating viral particle of any one of  claims 27 - 29 , wherein the mouse p16 promoter comprises a sequence corresponding to SEQ ID NO: 2. 
     
     
         31 . The conditionally replicating viral particle of any one of  claims 21 - 30 , wherein the viral particle further comprises the polynucleotide of any one of  claims 1 - 12 . 
     
     
         32 . A method for expressing a pro-apoptotic gene in a senescent cell comprising administering to the cell the polynucleotide of any one of  claims 1 - 12 , the viral vector of any one of  claims 13 - 17 , the viral particle of any one of  claim 16 - 18  or  21 - 31 , or the pharmaceutical composition of  claim 19 . 
     
     
         33 . A method for inducing apoptosis in a senescent cell comprising administering to the cell the polynucleotide of any one of  claims 1 - 12 , the viral vector of any one of  claims 13 - 17 , the viral particle of any one of  claim 16 - 18  or  21 - 31 , or the pharmaceutical composition of  claim 19 . 
     
     
         34 . The method of  claim 32  or  33  wherein the p16 promoter is activated in the senescent cell. 
     
     
         35 . The method of any one of  claims 32 - 34  wherein the cell is in vivo in a mammal. 
     
     
         36 . The method of any one of  claims 32 - 34  wherein the cell is in vitro. 
     
     
         37 . A method for expressing a conditionally replicating virus in a cell comprising infecting the cell with the viral particle of any one of  claim 16 - 18  or  21 - 31 , wherein the virus replicates in senescent cells but not in non-senescent cells. 
     
     
         38 . A method for inducing apoptosis in senescent cell in subjects in need thereof comprising administering to the subject the polynucleotide of any one of  claims 1 - 12 , the viral vector of any one of  claims 13 - 17 , the viral particle of any one of  claim 16 - 18  or  21 - 31 , or the pharmaceutical composition of  claim 19 .