Dual vector for inhibition of human immunodeficiency virus

Patent metadata

Field	Value
Publication number	US-2022016176-A1
Application number	US-202117368947-A
Country	US
Kind code	A1
Filing date	Jul 7, 2021
Priority date	Jul 15, 2009
Publication date	Jan 20, 2022
Grant date	—

Abstract

The present invention provides an expression vector for preventing or inhibiting HIV entry, fusion or replication in mammalian cells. In particular, the invention provides a recombinant retroviral vector that encodes an inhibitor of a HIV co-receptor, such as CCR5 or CXCR4, and a protein that inhibits HIV fusion to target cells and/or HIV replication. Pharmaceutical compositions comprising such constructs and methods of use thereof to prevent or treat HIV infection in a patient are also disclosed.

First claim

1 - 24 . (canceled)

25 . A method of treating or preventing HIV infection in a patient, comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising (i) an expression vector comprising a first nucleic acid sequence encoding a shRNA having the sequence of SEQ ID NO: 1, wherein the first nucleic acid sequence is operably linked to an H1 promoter, and a second nucleic acid sequence encoding a C46 protein that inhibits HIV fusion to a target cell, wherein the second nucleic acid sequence is operably linked to a UbiquitinC pol II promoter; and (ii) a pharmaceutically acceptable carrier,
wherein following administration of the pharmaceutical composition, the immune system of the patient is at least partially reconstituted with HIV-resistant cells.

26 . A method of treating or preventing HIV infection in a patient, comprising:
(i) transducing hematopoietic cells with an expression vector, the expression vector comprising a first nucleic acid sequence encoding a shRNA having the sequence of SEQ ID NO: 1, wherein the first nucleic acid sequence is operably linked to an H1 promoter, and a second nucleic acid sequence encoding a C46 protein, wherein the second nucleic acid sequence is operably linked to a UbiquitinC pol II promoter, and (ii) transplanting said transduced hematopoietic cells in the patient, wherein said transduced hematopoietic cells are resistant to HIV infection.

27 . The method of claim 26 , wherein said hematopoietic cells are hematopoietic progenitor/stem cells (HPSC), CD4+ T lymphocytes, CDS+ T lymphocytes, monocyte/macrophages, or combinations thereof.

28 . The method of claim 27 , wherein said transplanted HPSC generate granulocytes, monocyte/macrophages, and lymphocytes that are resistant to HIV infection.

29 . The method of claim 26 , wherein said hematopoietic cells are autologous or allogeneic.

30 . The method of claim 28 , wherein said granulocytes, monocyte/macrophages, and lymphocytes are resistant to infection by RS and X4 tropic strains of HIV.

31 . The method of claim 28 , wherein said granulocytes, monocyte/macrophages, and lymphocytes are resistant to infection by HAART-resistant HIV strains.

32 . The method of claim 26 , wherein the second nucleic acid sequence has the sequence of SEQ ID NO: 3.

33 . The method of claim 26 , wherein the C46 protein has an amino acid sequence having at least about 90% sequence identity to that of SEQ ID NO: 2.

34 . The method of claim 26 , wherein the first nucleic acid sequence and the second nucleic acid sequence are expressed in a ratio ranging from about 2:1 to about 10:1.

35 . The method of claim 34 , wherein the ratio ranges from about 2:1 to about 5:1.

36 . The method of claim 25 , wherein administration of the pharmaceutical composition causes a transduction of hematopoietic cells in the patient, the transduced hematopoietic cells having at least 30% less CCR5 receptors as compared with non-transduced cells and wherein the transduced hematopoietic cells express the C46 protein; and wherein the transduced hematopoietic cells reconstitute the immune system of the patient such that after transplantation, the transduced hematopoietic cells provide a continual source of at least one of granulocytes, monocytes/macrophages, or lymphocytes that are resistant to HIV infection.

37 . A method of treating or preventing HIV infection in a human patient, comprising:
(i) transducing hematopoietic cells with a lentiviral expression vector, the lentiviral expression vector comprising:
a first nucleic acid sequence encoding a shRNA having the sequence of SEQ ID NO: 1, wherein the first nucleic acid sequence is operably linked to an H1 promoter; and a second nucleic acid sequence encoding a C46 protein that inhibits HIV fusion to a target cell, wherein the second nucleic acid sequence is operably linked to a UbiquitinC pol II promoter; and
(ii) transplanting the transduced hematopoietic cells in the patient, the transduced hematopoietic cells having at least 30% less CCR5 receptors as compared with nontransduced cells and wherein the transduced hematopoietic cells express the C46 protein; and wherein the transduced hematopoietic cells reconstitute the immune system of the patient such that the transplanted transduced hematopoietic cells provide a continual source of at least one of granulocytes, monocytes/macrophages, or lymphocytes that are resistant to HIV infection.

38 . The method of claim 37 , wherein the first nucleic acid sequence and the second nucleic acid sequence are expressed in a ratio ranging from about 2:1 to about 10:1.

39 . The method of claim 38 , wherein the ratio ranges from about 2:1 to about 5:1.

Assignees

• Csl Behring Gene Therapy Inc
• Univ California

Inventors

• Chen Irvin
• An Dong Sung
• Millington Michelle
• Boyd Maureen
• Symonds Geoffrey P
• Breton Louis Randall

Classifications

• C12N2830/85

  mammalian · CPC title

• A61K48/0058

  Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct · CPC title

• C12N2320/31

  Combination therapy · CPC title

• C12N2740/16234

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title

• C12N2740/16071

  Demonstrated in vivo effect · CPC title