Combination vectors and methods for treating cancer
A composition for treating cancer is disclosed. The composition includes a lentiviral particle and an aminobisphosphonate drug. The lentiviral particle is capable of infecting a target cell, such as a cancer cell, and includes an envelope protein optimized for targeting such target cell and a viral vector. The viral vector includes a small RNA optimized to target an FDPS mRNA sequence. The aminobisphosphonate drug includes zoledronic acid.
1. A viral vector comprising a therapeutic cargo portion, wherein the therapeutic cargo portion comprises:
a first small RNA sequence that is capable of binding to a first pre-determined complementary mRNA sequence, wherein the first pre-determined complementary mRNA sequence comprises a FDPS mRNA sequence; and
a second small RNA sequence that is capable of binding to a second pre-determined complementary mRNA sequence, wherein the second pre-determined complementary mRNA sequence comprises a CD47 mRNA sequence or a cMyc mRNA sequence.
2. The viral vector of claim 1 , wherein the first small RNA sequence is under the control of a first promoter, and the second small RNA sequence is under the control of a second promoter.
3. The viral vector of claim 1 , wherein the therapeutic cargo portion further comprises a third small RNA sequence that is capable of binding to a third pre-determined complementary mRNA sequence, wherein the third pre-determined complementary mRNA sequence comprises a CD47 mRNA sequence or a cMyc mRNA sequence.
4. The viral vector of claim 3 , wherein the third small RNA sequence is under the control of a third promoter.
5. The viral vector of claim 3 , wherein the small RNA sequences are under the control of a single promoter.
6. The viral vector of claim 1 , wherein the first small RNA sequence comprises a miRNA or a shRNA.
7. The viral vector of claim 1 , wherein the first small RNA sequence comprises a sequence having at least 80%, or at least 85%, or at least 90%, or at least 95% percent identity with a FDPS small RNA sequence comprising
(SEQ ID NO: 1)
GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTCCAGGACTT
TTT;
(SEQ ID NO: 2)
GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAATCCTGCTT
TTT;
(SEQ ID NO: 3)
GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTACATGGCTT
TTT;
or
(SEQ ID NO: 4)
GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCCTTCTGCTT
TTT.
8. The viral vector of claim 7 , wherein the first small RNA sequence is selected from SEQ ID NOs: 1, 2, 3, or 4.
9. The viral vector of claim 1 , wherein the second small RNA sequence comprises a sequence having at least 80%, or at least 85%, or at least 90%, or at least 95% percent identity with a CD47 small RNA sequence comprising
(SEQ ID NO: 5)
GGTGAAACGATCATCGAGCCTCGAGGCTCGATGATCGTTTCACCTTTTT;
(SEQ ID NO: 6)
GCTACTGGCCTTGGTTTAACTCGAGTTAAACCAAGGCCAGTAGCTTTTT;
(SEQ ID NO: 7)
CCTCCTTCGTCATTGCCATCTCGAGATGGCAATGACGAAGGAGGTTTTT;
(SEQ ID NO: 8)
GCATGGCCCTCTTCTGATTCTCGAGAATCAGAAGAGGGCCATGCTTTTT;
or
(SEQ ID NO: 9)
GGTGAAACGATCATCGAGCTACTCGAGTAGCTCGATGATCGTTTCACCTT
TTT
or a cMyc small RNA sequence comprising
(SEQ ID NO: 10)
GCTTCACCAACAGGAACTATGCTCGAGCATAGTTCCTGTTGGTGAAGCTT
TT;
(SEQ ID NO: 11)
GCGAACACACAACGTCTTGGACTCGAGTCCAAGACGTTGTGTGTTCGCTT
TT;
(SEQ ID NO: 12)
GACATGGTGAACCAGAGTTTCCTCGAGGAAACTCTGGTTCACCATGTCTT
TTT;
(SEQ ID NO: 13)
GAGAATGTCAAGAGGCGAACACTCGAGTGTTCGCCTCTTGACATTCTCTT
TTT;
or
(SEQ ID NO: 14)
GCTCATTTCTGAAGAGGACTTCTCGAGAAGTCCTCTTCAGAAATGAGCTT
TTT.
10. The viral vector of claim 9 , wherein the second small RNA sequence is selected from SEQ ID NOs: 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14.
11. The viral vector of claim 3 , wherein the third small RNA sequence comprises a sequence having at least 80%, or at least 85%, or at least 90%, or at least 95% percent identity with a CD47 small RNA sequence comprising SEQ ID NOs: 5, 6, 7, 8, or 9 or a cMyc small RNA sequence comprising SEQ ID NOs: 10, 11, 12, 13, or 14.
12. The viral vector of claim 11 , wherein the third small RNA sequence is selected from SEQ ID NOs: 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14.
13. The viral vector of any one of claims 1 and 2 - 12 , wherein the viral vector is a lentiviral vector.
14. A lentiviral particle capable of infecting a target cell, the lentiviral particle comprising:
a. an envelope protein optimized for infecting the target cell; and
b. the viral vector according to claim 1 .
15. A composition comprising:
a. the lentiviral particle according to claim 14 ; and
b. an aminobisphosphonate drug.
16. The composition of claim 15 , wherein the aminobisphosphonate drug is zoledronic acid.
17. A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 15 or 16 .
18. A method of treating cancer in a subject, the method comprising administering to the subject:
a. a therapeutically effective amount of the lentiviral particle according to claim 14 ; and
b. a therapeutically effective amount of an aminobisphosphonate drug.
19. A method of preventing cancer in a subject, the method comprising administering to the subject:
a. an effective amount of the lentiviral particle according to claim 14 ; and
b. an effective amount of an aminobisphosphonate drug.
20. The method of claim 18 or 19 , wherein the aminobisphosphonate drug is zoledronic acid.
21. The method of claim 18 or 19 , wherein steps (a) and (b) are carried out simultaneously.
22. The method of claim 18 or 19 , wherein a defined period of time elapses between step (a) and step (b).
23. The method of claim 18 or 19 , wherein the therapeutically effective amount of the lentiviral particle comprises a plurality of single doses of the lentiviral particle.
24. The method of claim 18 or 19 , wherein the therapeutically effective amount of the aminobisphosphonate drug comprises a single dose of the aminobisphosphonate drug.