GENE THERAPY VECTORS FOR ADRENOLEUKODYSTROPHY AND ADRENOMYELONEUROPATHY

• US 20130004471A1
• Filed: 06/08/2012
• Published: 01/03/2013
• Est. Priority Date: 06/10/2011
• Status: Active Grant

• Current Assignee: bluebird bio, Inc.
• Original Assignee: bluebird bio, Inc.
• Inventors: Veres, Gabor, Denaro, Maria Joann, Finer, Mitchell Howard
• Granted Patent: US 8,858,928 B2
• Time in Patent Office: Days
• US Class Current: 424/93.21
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 35/51 Umbilical cord; Umbilical cord blood; Umbilical stem cells
• CPC Class Codes: A61K 38/177 Receptors; Cell surface antigens; Cell surface determinants
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61K 48/0058 Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2740/15043 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2740/16043 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2800/24 Vectors characterised by the absence of particular element, e.g. selectable marker, viral origin of replication
• CPC Class Codes: C12N 2830/00 Vector systems having a special element relevant for transcription
• CPC Class Codes: C12N 2830/008 cell type or tissue specific enhancer/promoter combination
• CPC Class Codes: C12N 2830/50 regulating RNA stability, not being an intron, e.g. poly A signal
• CPC Class Codes: C12N 2830/60 from viruses
• CPC Class Codes: C12N 2840/00 Vectors comprising a special translation-regulating system
• CPC Class Codes: C12N 5/0686 Kidney cells
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

The present invention provides compositions comprising retroviral vectors, transduced cells, and methods of using the same for gene therapy. In particular, the present invention relates to lentiviral vectors and cells transduced with those vectors to provide gene therapy to subjects having an adrenoleukodystrophy and/or adrenomyeloneuropathy.

Claims

1. A vector comprising:

(a) a left (5′

) retroviral LTR;

(b) a central polypurine tract/DNA flap (cPPT/FLAP);

(c) a retroviral export element;

(e) a promoter active in a microglial cell, operably linked to a polynucleotide encoding an ATP-binding cassette, sub-family D, member 1 (ABCD1) polypeptide; and

(f) a right (3′

) retroviral LTR;

wherein the vector does not comprise a woodchuck post-transcriptional regulatory element (WPRE).

2. The vector of claim 1, wherein the vector is a lentivirus vector.

3. The vector of claim 2, wherein the lentivirus is HIV.

4. The vector of claim 2, wherein the lentivirus is HIV-1.

5. The vector of claim 1, wherein the promoter of the 5′

LTR is replaced with a heterologous promoter selected from the group consisting of;

a cytomegalovirus (CMV) promoter, a Rous Sarcoma Virus (RSV) promoter, or an Simian Virus 40 (SV40) promoter.

11. The vector of claim 1, wherein the 3′

LTR comprises one or more modifications.

13. The vector of claim 1, wherein the 3′

LTR is a self-inactivating (SIN) LTR.

16. The vector of claim 1, wherein the promoter comprises a myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted (MND) promoter or transcriptionally active fragment thereof.

17. The vector of claim 1, wherein the polynucleotide encoding ABCD1 polypeptide is a cDNA.

18. The vector of claim 17, wherein the cDNA comprises an optimized Kozak sequence.

27. A mammalian cell comprising a vector according to claim 1.

28. A packaging cell comprising:

a first polynucleotide encoding gag, a second polynucleotide encoding pol, a third polynucleotide encoding env, and a vector according to claim 1.

29. A producer cell comprising a vector according to claim 1.

30. A vector particle produced by the producer cell of claim 29.

34. A host cell transduced with the vector according to claim 1.

39. A method of treating adrenoleukodystrophy or adrenomyeloneuropathy, comprising administering to a subject a cell transduced with a vector according to claim 1.

40. The method of claim 39, wherein the cell is an embryonic stem cell, a somatic stem cell, or a progenitor cell.

41. The method of claim 39, wherein the cell is a hematopoietic stem cell.

6-10. -10. (canceled)

12. (canceled)

14-15. -15. (canceled)

19-20. -20. (canceled)

21. A lentiviral vector comprising:

(a) a left (5′

) LTR;

(b) a cPPT/FLAP;

(c) an RRE;

(d) a MND promoter operably linked to a polynucleotide encoding a human ABCD1 polypeptide;

(e) a right (3′

) LTR; and

(f) a polyadenylation sequence;

wherein the vector does not comprise a woodchuck post-transcriptional regulatory element (WPRE).

22. The lentiviral vector of claim 21, comprising a Psi (Ψ

) packaging signal.

23. The lentiviral vector of claim 21, wherein the polyadenylation sequence is a bovine growth hormone polyadenylation or signal rabbit β

-globin polyadenylation sequence.

24-25. -25. (canceled)

26. A lentiviral vector comprising:

(a) a left (5′

) HIV-1 LTR;

(b) a Psi (Ψ

) packaging signal;

(c) a cPPT/FLAP;

(d) an RRE;

(e) a MND promoter, operably linked to a cDNA encoding a human ABCD1 polypeptide;

(f) a right (3′

) self-inactivating (SIN) HIV-1 LTR; and

(g) a rabbit β

-globin polyadenylation sequence;

wherein the vector does not comprise a woodchuck post-transcriptional regulatory element (WPRE).

31-33. -33. (canceled)

35-38. -38. (canceled)