E6AP antisense constructs and methods of use
AssigneeMitotix, Inc.
InventorsPeggy L. Beer-Romero, Giulio Draetta, Mark Rolfe
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Abstract
The present invention relates to the discovery that antisense nucleic acids complimentary to an E6AP gene can be used to regulate cellular p53 levels. In general the invention features E6AP antisense constructs which, by inhibiting E6AP activity, can modulate cellular p53 levels in both p53+ transformed cells and in normal cells. The invention also provides methods for treating papillomavirus (PV) induced condition, methods for regulating cellular p53 levels and methods for regulating cellular proliferation.
Claims83
A purified preparation of an antisense nucleic acid which specifically hybridizes under physiological conditions to mRNA transcribed by gene encoding an E6-associated protein (an E6AP gene) and inhibits expression of said E6AP gene and wherein said antisense nucleic acid is further selected from the group consisting of a synthetic oligonucleotide, a single-stranded oligonucleotide, a linear oligonucleotide, an oligonucleotide which is 20-50 nucleotides in length, a DNA analog resistant to nuclease degradation, and combinations thereof.
An expression construct comprising a gene transcribable as an antisense nucleic acid which specifically hybridizes to mRNA expressed by a gene encoding an E6-associated protein (an E6AP gene) and inhibits expression of said E6AP gene under physiological conditions.
A pharmaceutical composition comprising an antisense nucleic acid which specifically hybridizes to mRNA expressed by a gene encoding an E6-associated protein (an E6AP gene) and inhibits expression of E6AP gene under physiological conditions, which antisense nucleic acid is formulated in a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising an expression construct including a gene transcribable as an antisense nucleic acid which specifically hybridizes to mRNA expressed by a gene encoding an E6-associated protein (an E6AP gene) and inhibits expression of said E6AP gene under physiological conditions, which expression construct is formulated in a pharmaceutically acceptable carrier.
An E6AP antisense nucleic acid having the nucleotide sequence of SEQ ID No:2.
An E6AP antisense nucleic acid having the nucleotide sequence of SEQ ID No:4.
An E6AP antisense nucleic acid having the nucleotide sequence of SEQ ID No:6.
A method of increasing a cellular p53 level of an epithelial cell comprising:
- introducing into an epithelial cell by topical application to said cell an E6AP antisense construct in an amount sufficient to produce in the cell a population of antisense nucleic acids which specifically hybridize to mFNA expressed by a gene encoding an E6-associated protein (an E6AP gene) under physiological conditions and which inhibit expression of said E6AP gene, wherein inhibition of expression of said E6AP gene results in a statistically significant increase in the cellular p53 level compared to a control population of cells.
A method of treating papillomavirus (PV) induced conditions comprising:
- administering to an animal, by topical application to cells infected with said papillomavirus, an E6AP antisense construct which inhibits expression of an E6AP gene in an amount sufficient to have a cytostatic or cgtotoxic effect on the PV-infected cells.
A method of inhibiting proliferation of a cells expressing p53 comprising administering to an animal, by topical application to said cells, an E6AP antisense construct in an amount sufficient to produce in said cells a population of antisense nucleic acids which specifically hybridize to mRNA transcribed by a gene encoding an E6-associated protein (an .sub.-- E6AP gene) under physiological conditions, which antisense nucleic acids inhibit expression of said E6AP gene inhibit proliferation of said cells.
Dependencies are inferred from the claim text.