Syncytial oncolytic herpes simplex mutants as potent cancer therapeutics
AssigneeResearch Institute At Nationwide Children's Hospital
InventorsTimothy P. Cripe, Kevin A. Cassady, Pin-Yi Wang, Julia K. Halley
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Abstract
The disclosure provides a non-natural herpes simplex virus (“HSV”), compositions comprising, or alternatively consisting essentially of, or yet further consisting of the HSV, and methods of producing the HSV, or infecting a cell with the HSV. Also provided herein are methods of treating cancer or inhibiting the growth or metastasis of cancer cell in a subject in need thereof.
Claims16
A non-natural herpes simplex virus (“HSV”), wherein the virus comprises at least one mutation in a virulence gene selected from:
- (a) an alanine-to-threonine mutation at position 151 of the gE protein, wherein the alanine-to-threonine mutation at position 151 is with respect to SEQ ID NO:
- 19,
- (b) an arginine-to-histidine mutation at position 258 of the ICP0 protein, wherein the arginine-to-histidine mutation at position 258 is with respect to SEQ ID NO:
- 26,
- (c) an alanine-to-threonine mutation at position 376 of the DNA packaging terminase subunit 1 protein, wherein the alanine-to-threonine mutation at position 376 is with respect to SEQ ID NO:
- 42, or
- (d) a threonine-to-methionine mutation at position 1155 of the ICP8 protein, wherein the threonine-to-methionine mutation at position 1155 is with respect to SEQ ID NO:
- 34;
- and wherein the non-natural HSV has improved lytic activity compared to an HSV that does not comprise the at least one mutation.
A composition comprising a carrier and a non-natural herpes simplex virus (“HSV”), wherein the virus comprises at least one mutation in a virulence gene selected from:
- (a) an alanine-to-threonine mutation at position 151 of the gE protein, wherein the alanine-to-threonine mutation at position 151 is with respect to SEQ ID NO:
- 19,
- (b) an arginine-to-histidine mutation at position 258 of the ICP0 protein, wherein the arginine-to-histidine mutation at position 258 is with respect to SEQ ID NO:
- 26,
- (c) an alanine-to-threonine mutation at position 376 of the DNA packaging terminase subunit 1 protein, wherein the alanine-to-threonine mutation at position 376 is with respect to SEQ ID NO:
- 42, or
- (d) a threonine-to-methionine mutation at position 1155 of the ICP8 protein, wherein the threonine-to-methionine mutation at position 1155 is with respect to SEQ ID NO:
- 34;
- and wherein the non-natural HSV has improved lytic activity compared to an HSV that does not comprise the at least one mutation.
A cell infected with a non-natural herpes simplex virus (“HSV”), wherein the virus comprises at least one mutation in a virulence gene selected from:
- (a) an alanine-to-threonine mutation at position 151 of the gE protein, wherein the alanine-to-threonine mutation at position 151 is with respect to SEQ ID NO:
- 19,
- (b) an arginine-to-histidine mutation at position 258 of the ICP0 protein, wherein the arginine-to-histidine mutation at position 258 is with respect to SEQ ID NO:
- 26,
- (c) an alanine-to-threonine mutation at position 376 of the DNA packaging terminase subunit 1 protein, wherein the alanine-to-threonine mutation at position 376 is with respect to SEQ ID NO:
- 42, or
- (d) a threonine-to-methionine mutation at position 1155 of the ICP8 protein, wherein the threonine-to-methionine mutation at position 1155 is with respect to SEQ ID NO:
- 34;
- and wherein the non-natural HSV has improved lytic activity compared to an HSV that does not comprise the at least one mutation.
A method to infect a cell, comprising contacting the cell with a non-natural herpes simplex virus (“HSV”), wherein the virus comprises at least one mutation in a virulence gene selected from:
- (a) an alanine-to-threonine mutation at position 151 of the gE protein, wherein the alanine-to-threonine mutation at position 151 is with respect to SEQ ID NO:
- 19,
- (b) an arginine-to-histidine mutation at position 258 of the ICP0 protein, wherein the arginine-to-histidine mutation at position 258 is with respect to SEQ ID NO:
- 26,
- (c) an alanine-to-threonine mutation at position 376 of the DNA packaging terminase subunit 1 protein, wherein the alanine-to-threonine mutation at position 376 is with respect to SEQ ID NO:
- 42, or
- (d) a threonine-to-methionine mutation at position 1155 of the ICP8 protein, wherein the threonine-to-methionine mutation at position 1155 is with respect to SEQ ID NO:
- 34;
- and wherein the non-natural HSV has improved lytic activity compared to an HSV that does not comprise the at least one mutation.
A method for inhibiting the growth or metastasis of cancer cell, comprising contacting the cell with an effective amount of a non-natural herpes simplex virus (“HSV”), wherein the virus comprises at least one mutation in a virulence gene selected from:
- (a) an alanine-to-threonine mutation at position 151 of the gE protein, wherein the alanine-to-threonine mutation at position 151 is with respect to SEQ ID NO:
- 19,
- (b) an arginine-to-histidine mutation at position 258 of the ICP0 protein, wherein the arginine-to-histidine mutation at position 258 is with respect to SEQ ID NO:
- 26,
- (c) an alanine-to-threonine mutation at position 376 of the DNA packaging terminase subunit 1 protein, wherein the alanine-to-threonine mutation at position 376 is with respect to SEQ ID NO:
- 42, or
- (d) a threonine-to-methionine mutation at position 1155 of the ICP8 protein, wherein the threonine-to-methionine mutation at position 1155 is with respect to SEQ ID NO:
- 34;
- and wherein the non-natural HSV has improved lytic activity compared to an HSV that does not comprise the at least one mutation.
A method for treating cancer in a subject, comprising administering to the subject an effective amount of a non-natural herpes simplex virus (“HSV”), wherein the virus comprises at least one mutation in a virulence gene selected from:
- (a) an alanine-to-threonine mutation at position 151 of the gE protein, wherein the alanine-to-threonine mutation at position 151 is with respect to SEQ ID NO:
- 19,
- (b) an arginine-to-histidine mutation at position 258 of the ICP0 protein, wherein the arginine-to-histidine mutation at position 258 is with respect to SEQ ID NO:
- 26,
- (c) an alanine-to-threonine mutation at position 376 of the DNA packaging terminase subunit 1 protein, wherein the alanine-to-threonine mutation at position 376 is with respect to SEQ ID NO:
- 42, or
- (d) a threonine-to-methionine mutation at position 1155 of the ICP8 protein, wherein the threonine-to-methionine mutation at position 1155 is with respect to SEQ ID NO:
- 34;
- and wherein the non-natural HSV has improved lytic activity compared to an HSV that does not comprise the at least one mutation.
A kit comprising a non-natural herpes simplex virus (“HSV”), wherein the virus comprises at least one mutation in a virulence gene selected from:
- (a) an alanine-to-threonine mutation at position 151 of the gE protein, wherein the alanine-to-threonine mutation at position 151 is with respect to SEQ ID NO:
- 19,
- (b) an arginine-to-histidine mutation at position 258 of the ICP0 protein, wherein the arginine-to-histidine mutation at position 258 is with respect to SEQ ID NO:
- 26,
- (c) an alanine-to-threonine mutation at position 376 of the DNA packaging terminase subunit 1 protein, wherein the alanine-to-threonine mutation at position 376 is with respect to SEQ ID NO:
- 42, or
- (d) a threonine-to-methionine mutation at position 1155 of the ICP8 protein, wherein the threonine-to-methionine mutation at position 1155 is with respect to SEQ ID NO:
- 34;
- and wherein the non-natural HSV has improved lytic activity compared to an HSV that does not comprise the at least one mutation and instructions for use.
Dependencies are inferred from the claim text.