Hexon Tat-PTD modified adenovirus and uses thereof
The invention provides a hexon Tat-PTD modified adenovirus, a gene delivery vector based on the modified adenovirus that enhances gene delivery efficiency, and an oncolytic agent based on the modified adenovirus that enhances tumor cell killing efficiency and improves therapeutic outcome.
1. An adenovirus, comprising at least one of (i) an adenovirus hexon protein which is modified to comprise at least one protein transduction domain of the Tat protein from Human Immunodeficiency Virus (HIV) and (ii) a recombinant nucleic acid molecule encoding said modified adenovirus hexon protein, wherein said modified adenovirus hexon protein comprises the amino acid sequence of SEQ ID NO:2 inserted into hypervariable region 5 of the adenovirus hexon protein.
2. The adenovirus according to claim 1 , wherein said modified adenovirus hexon protein comprises the amino acid sequence according to SEQ ID NO:3.
3. The adenovirus of claim 1 , wherein the adenovirus is selected from the group consisting of serotype-2 (Ad2), -3 (Ad3), -7(Ad7), -11 (Ad11), -17 (Ad17), -35 (Ad35), -41 (Ad41), -48 (Ad48) and their derivatives.
4. The adenovirus of claim 1 , wherein the adenovirus is an adenovirus serotype 5 comprising a fiber and/or fiber knob of other adenovirus serotypes, in place of the adenovirus serotype 5 fiber and/or fiber knob.
5. The adenovirus of claim 4 , comprising the fiber and/or fiber knob of adenovirus serotypes selected from serotypes Ad2, Ad3, Ad7, Ad11, Ad17, Ad35, Ad41 and Ad48.
6. The adenovirus of claim 1 , wherein the adenovirus is operatively modified by a heterologous nucleotide sequence, which codes for the amino acid sequence of SEQ ID NO:2 inserted into hypervariable region 5 of the adenovirus hexon protein.
7. The adenovirus of claim 1 , wherein E1 and/or E3 and/or E4 regions of the adenovirus are deleted.
8. The adenovirus of claim 1 , wherein the adenovirus is of serotype 5 and wherein said adenovirus hexon protein is derived from serotype Ad2, Ad3, Ad35, Ad11, Ad17, Ad41, Ad48 and their derivatives.
9. The adenovirus of claim 1 , further comprising at least one heterologous nucleic acid molecule in addition to any recombinant nucleic acid molecule encoding an adenovirus hexon protein modified to comprise the amino acid sequence of SEQ ID NO:2 inserted into hypervariable region 5 of the adenovirus hexon protein.
10. The adenovirus of claim 1 , wherein an E1a gene of the adenovirus is controlled by a tissue-specific promoter and/or a tumor-specific promoter, and/or is a mutated E1a gene.
11. The adenovirus of claim 1 , wherein the adenovirus comprises one or more therapeutic genes.
12. The adenovirus of claim 1 , wherein an E1a gene is under control of a tissue-specific or tumor-specific promoter, and comprises one or more therapeutic genes.
13. The adenovirus of claim 12 , wherein the tissue specific promoter is selected from the group consisting of the prostate cell-specific PPT promoter, the neuroendocrine cell-specific CgA promoter, and the neuroblastoma-specific SCG3, SCG2, NESP-55 promoters; and the tumor-specific promoter is selected from the group consisting of the hTERT, Cox-2, survivin and E2F-1 promoters.
14. The adenovirus of claim 11 , wherein the therapeutic genes are selected from the group consisting of the genes encoding CD40L, HRG, HP-NAP, GM-CSF, HSV-TK and cytosine deaminase, and codon-optimized versions thereof.
15. A pharmaceutical composition comprising the adenovirus of claim 1 , and optionally pharmaceutically acceptable buffers, carriers and excipients.
16. The pharmaceutical composition of claim 15 , wherein the composition is derived/generated by the said adenovirus.
17. A method of treating cancer in a subject, comprising administrating to the subject a therapeutically effective amount of adenovirus according to claim 1 .
18. A method according to claim 17 , further comprising additional treatment of cancer.
19. A method according to claim 18 , wherein said additional treatment of cancer is selected from surgery, traditional Chinese medicine, acupuncture, chemotherapy, radiotherapy, therapeutic antibodies.
20. A method of delivering a heterologous nucleic acid molecule to a mammalian cell, comprising bringing said mammalian cell into contact with an adenovirus according to claim 1 under conditions allowing delivery of said heterologous nucleic acid molecule to said mammalian cell.
21. A method of treating, or ameliorating a disease or condition in a subject, comprising delivering a heterologous nucleic acid molecule to at least one cell of said subject by bringing said cell into contact with an adenovirus according to claim 1 under conditions allowing delivery of said heterologous nucleic acid molecule to said cell, wherein said heterologous nucleic acid molecule is effective to at least in part treat or ameliorate the disease or condition.
22. A method according to claim 21 , wherein said disease or condition is a cancer.
23. A method according to claim 21 , wherein said disease or condition is influenced by a genetic factor and said heterologous nucleic acid molecule is effective to at least in part counter or compensate for said genetic factor.
24. The adenovirus according to claim 10 , wherein the mutated E1a gene is E1a-delta24.