Gene vector for inducing transgene-specific immune tolerance
A gene vector adapted for transient expression of a transgene in a peripheral organ cell comprising a regulatory sequence operably linked to a transgene wherein the regulatory sequence prevents or reduces expression of said transgene in hematopoietic lineage cells.
1. A gene vector adapted for transient expression of a transgene in a liver cell comprising a regulatory sequence operably linked to the transgene, wherein the regulatory sequence prevents or reduces expression of said transgene in hematopoietic lineage antigen presenting cells, wherein the transgene is operably linked to a hepato-specific promoter, wherein the vector is an integration defective lentiviral vector (IDLV), and wherein the regulatory sequence comprises one or more target sequences each of which is independently selected from sequences targeted by miR-142, miR-155, miR-223 or miR-181.
2. The vector according to claim 1 , wherein the IDLV vector is derived from HIV.
3. The vector according to claim 1 , wherein the target sequence is a sequence targeted by miR-142.
4. The vector according to claim 3 , wherein the regulatory sequence comprises four copies of a miR-142 target sequence.
5. The vector according to claim 1 , wherein at least one or more of the target sequences is fully or partially complementary to the miR-142, miR-155, miR-223 or miR-181 sequence.
6. The vector according to claim 1 , wherein the transgene product is a therapeutic protein.
7. The vector according to claim 1 , wherein the trans gene product is an antigen.
8. The vector according to claim 7 , wherein the antigen is selected from the group consisting of an endogenous antigen, an exogenous antigen, an alloantigen and an autoantigen.
9. The vector according to claim 8 , wherein the antigen is an exogenous antigen.
10. The vector according to claim 1 , wherein the hepato-specific promoter is a promoter selected from the group of albumin promoter, trans-thyretin promoter, alpha1-antitrypsin promoter, synthetic apoE/alpha1-antitrypsin promoter and synthetic ET promoter.
11. The vector according to claim 1 , wherein the vector is in the form of a viral vector particle.
12. A set of DNA constructs for producing the vector particle of claim 11 comprising a packagable vector genome, gag, pol and env or functional substitutes thereof.
13. The set of DNA constructs according to claim 12 , wherein said constructs encode a defective integrase.
14. The set of DNA constructs according to claim 12 , wherein said constructs comprise altered LTR sites and wherein the altered LTR sites prevent integration of the lentiviral vector genome.
15. A pharmaceutical composition comprising the vector of claim 1 .
16. An isolated cell infected or transduced with the vector of claim 1 .
17. The vector according to claim 1 for use in inducing or enhancing immunological tolerance against an antigen in a subject.
18. The vector according to claim 1 , wherein the antigen is an exogenous antigen administered as part of a protein replacement therapy.
19. The vector according to claim 1 , wherein at least one or more of the target sequence has perfect complementarity to the miR-142, miR-155, miR-223 or miR-181 sequence.
20. The vector according to claim 19 , wherein the vector includes more than one copy of an miRNA target sequence.
21. A pharmaceutical composition comprising the viral vector particle of claim 11 .
22. An isolated cell infected or transduced with the viral vector particle of claim 11 .
23. The viral vector particle according to claim 11 , for use in inducing or enhancing immunological tolerance against an antigen in a subject.
24. The viral vector particle according to claim 11 , wherein the transgene product is an antigen, and wherein the antigen is an exogenous antigen administered as part of a protein replacement therapy.