Composition comprising a gene vector that selectively depletes P16 positive senescent cells
View Patent ↗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.
1. A composition comprising a conditionally replicating virus in a pharmaceutically compatible excipient, wherein the conditionally replicating virus has a recombinant genome construct in which a replication gene for the virus is placed under transcriptional control of a heterologous promoter,
wherein the heterologous promoter is the p16 promoter,
wherein when the conditionally replicating virus is applied to a mixed cell population comprising target cells that express p16, the p16 promoter causes the virus to replicate preferentially in the target cells, thereby causing lysis of the target cells and selectively depleting them from the cell population.
2. The composition of claim 1 , wherein the genome construct of the conditionally replicating virus comprises more than one heterologous promoter.
3. The composition of claim 1 , wherein the genome construct of the conditionally replicating virus comprises a replication gene for the virus placed under transcriptional control of a chemically inducible promoter.
4. The composition of claim 1 , wherein replication of the virus is tissue specific.
5. The composition of claim 1 , wherein the conditionally replicating virus is an adenovirus.
6. The composition of claim 1 , wherein the conditionally replicating virus is a lentivirus, and the replication gene under transcriptional control of the p16 promoter is selected from gag, pol and env.
7. The composition of claim 1 , wherein the nucleotide sequence of the p16 promoter comprises SEQ. ID NO:1.
8. The composition of claim 1 , wherein the nucleotide sequence of the p16 promoter comprises SEQ. ID NO:2.
9. The composition of claim 1 , wherein the genome of the conditionally replicating virus further comprises a caspase gene under transcriptional control of the p16 promoter.
10. A method of selectively depleting senescent cells from a mixed cell population or tissue, comprising combining the tissue with a composition according to claim 1 such that the conditionally replicating virus replicates in the senescent cells in the mixed cell population or tissue.