Vector system

1. A lentiviral vector genome comprising three nucleotides of interest (NOIs) operably linked by one or more Internal Ribosome Entry Site(s) (IRES), wherein the NOIs encode tyrosine hydroxylase (TH), GTP-cyclohydrolase I (GTP-CH1) and aromatic amino acid dopa decarboxylase (AADC).

2. The genome according to claim 1 , wherein the lentiviral vector genome is an HIV lentiviral vector genome.

3. The genome according to claim 1 , wherein the lentiviral vector genome is a non-primate lentiviral vector genome.

4. The genome according to claim 1 , wherein at least one of the NOIs is operably linked to a promoter or promoter element(s).

5. The genome according to claim 1 , which lacks the rev responsive element (RRE).

6. The genome according to claim 1 , further comprising a cPPT sequence.

7. The genome according to claim 1 , further comprising a post-transcriptional regulatory element or a translational enhancer.

8. The genome according to claim 1 , wherein at least one of the NOIs is codon optimized.

9. The genome according to claim 3 , wherein the non-primate lentiviral vector genome is an EIAV lentiviral vector genome.

10. A vector system comprising a lentiviral vector genome comprising two or more nucleotides of interest (NOIs) operably linked by one or more Internal Ribosome Entry Site(s) (IRES), wherein the vector system further comprises: (i) a nucleotide sequence coding for lentiviral gag and pol proteins; and (ii) nucleotide sequence(s) encoding an env protein, and wherein the lentiviral vector genome is longer than the lentivirus wild type genome.

11. The vector system according to claim 10 , which is an EIAV vector system.

12. The vector system according to claim 10 , which is devoid of any additional lentiviral functional genes other than the nucleotides encoding lentiviral gag and pol proteins.

13. The vector system according to claim 10 , which is pseudotyped with at least part of a heterologous env protein.

14. The vector system according to claim 10 , wherein the lentiviral vector genome comprises a packaging signal.

15. A method for producing a lentiviral particle comprising introducing into a producer cell the vector system of claim 10 , thereby producing a lentiviral particle.

16. The vector system according to claim 13 , in which the heterologous env protein is Rabies-G or VSV G.

17. The method according to claim 15 , wherein the nucleotide sequence coding for lentiviral gag and pol is codon optimized for expression in the producer cell.

18. The method according to claim 15 , wherein the lentiviral vector genome comprises a packaging signal.

19. A lentiviral particle produced by the method of claim 15 , wherein the particle comprises the two or more NOIs, operably linked by one or more IRES(s).

20. A cell in vitro which has been transduced with the lentiviral particle of claim 19 .

21. A tricistronic cassette comprising a nucleotide sequence which encodes TH, a nucleotide sequence which encodes GTP-CH1, and a nucleotide sequence which encodes AADC, operably linked to two or more IRES(s).

22. The tricistronic cassette of claim 21 , wherein at least one of the nucleotides sequences is codon optimized.

23. The cassette of claim 21 , wherein the IRES is a viral IRES.

24. The cassette of claim 21 , wherein the IRES is a cellular IRES.

25. The cassette of claim 23 , wherein the viral IRES is from a picornavirus.

26. The cassette of claim 25 , wherein the picornavirus is encephalomyocarditis virus (EMCV) or poliovirus (PV).

27. The cassette of claim 24 , wherein the cellular IRES is FGF2 IRES or NRF IRES.

28. A lentiviral vector genome comprising three or more NOIs operably linked by two or more Internal Ribosome Entry Sites (IRESs), wherein each NOI encodes a protein associated with a neurodegenerative disorder.

29. The genome according to claim 28 , wherein the lentiviral vector genome is an HIV lentiviral vector genome.

30. The genome according to claim 28 , wherein the lentviral vector genome is a non-primate lentiviral vector genome.

31. The genome according to claim 28 , wherein each NOI encodes a protein selected from the group consisting of TH, GTP-CH1, AADC, and VMAT2.

32. The genome according to claim 28 , wherein at least one of the NOIs is operably linked to a promoter or promoter element(s).

33. The genome according to claim 28 , which lacks the rev responsive element (RRE).

34. The genome according to claim 28 , further comprising a cPPT sequence.

35. The genome according to claim 28 , further comprising a post-transcriptional regulatory element or a translational enhancer.

36. The genome according to claim 28 , wherein the NOIs encode TH, GTP-CH1 and AADC.

37. The genome according to claim 28 , wherein the genome is a self-inactivating genome.

38. A vector system comprising the genome according to claim 28 , wherein the vector system further comprises (i) a nucleotide sequence coding for lentiviral gag and pol proteins; and (ii) nucleotide sequence(s) coding for an env protein.

39. The genome according to claim 30 , wherein the non-primate lentiviral vector genome is an EIAV lentiviral vector genome.

40. The genome according to claim 31 , wherein at least one of the NOIs is codon optimized.

41. A vector system comprising the genome according to claim 37 .

42. The vector system according to claim 38 , wherein the lentiviral vector genome is longer than the lentivirus wild type genome.

43. The vector system of claim 38 , which is an EIAV vector system.

44. The vector system according to claim 38 , which is devoid of any additional lentiviral functional genes other than the nucleotide sequence coding for lentiviral gag and pol proteins.

45. The vector system according to claim 38 , which is pseudotyped with at least part of a heterologous env protein.

46. The vector system according to claim 38 , wherein the genome comprises a packaging signal.

47. A method for producing a lentiviral particle comprising introducing into a producer cell the vector system of claim 38 , thereby producing a lentiviral particle.

48. The vector system according to claim 45 , in which the heterologous env protein is Rabies-G or VSV G.

49. The method according to claim 47 , wherein the nucleotide sequence coding for lentiviral gag and pol is codon optimized for expression in the producer cell.

50. The method according to claim 47 , wherein the genome comprises a packaging signal.

51. A lentiviral particle produced by the method of claim 47 , which comprises the three or more NOIs, operably linked by two or more IRESs, wherein each NOI encodes a protein associated with a neurodegenerative disorder.

52. A cell in vitro which has been transduced with the lentiviral particle according to claim 51 .