Gene vector
A gene vector for use in gene therapy comprising at least one miRNA sequence target operably linked to a nucleotide sequence having a corresponding miRNA in a hematopoietic progenitor cell (HSPC) or hematopoietic stem cell (HSC) which prevents or reduces expression of the nucleotide sequence in a HSPC or HSC but not in a differentiated cell.
1. A gene vector for use in gene therapy for transduction or transfection of hematopoietic stem or progenitor cells, the gene vector comprising at least one mir-130a and/or mir-126 target sequence operably linked to a nucleotide sequence encoding a transgene selected from an immunomodulatory molecule, lysosomal enzyme galactocerebrosidase, and gp91 phox, such that:
with respect to hematopoietic stem cells or hematopoietic progenitor cells transduced or transfected with the vector, expression of the transgene is prevented or reduced by endogenous mir-130a and/or mir-126, and
with respect to differentiated myeloid and lymphoid progeny of the hematopoietic stem cells or hematopoietic progenitor cells, expression of the transgene occurs.
2. The gene vector according to claim 1 comprising at least one mir-130a target sequence and at least one mir-126 target sequence.
3. The gene vector according to claim 1 , wherein the vector is a viral vector.
4. The gene vector according to claim 1 , wherein the vector is derivable from a lentivirus.
5. The gene vector according to claim 1 , wherein the vector comprises a tissue specific promoter.
6. The gene vector according to claim 5 , wherein the tissue specific promoter is selected from the group consisting of CD11b, c-Fes, CYBB, and TEK.
7. The gene vector according to claim 1 , wherein the immunomodulatory molecule is interferon-alpha.
8. A pharmaceutical composition comprising the gene vector according to claim 1 .
9. A gene vector according to claim 2 , wherein the vector has twice as many copies of the mir-130a target sequence as copies of the mir-126 target sequence.
10. The gene vector according to claim 5 , wherein the promoter promotes expression in cells of myeloid lineage.
11. The gene vector according to claim 5 , wherein the promoter is TEK (Tie2).
12. The gene vector according to claim 11 , wherein the immunomodulatory molecule is interferon alpha.
13. A gene vector comprising a TEK (Tie2) promoter and at least one mir-130a and/or mir-126 target sequence operably linked to a nucleotide sequence encoding interferon-alpha, such that:
with respect to hematopoietic stem cells or hematopoietic progenitor cells transduced or transfected with the vector, expression of the interferon-alpha is prevented or reduced by endogenous mir-130a and/or mir-126, and
with respect to differentiated myeloid and lymphoid progeny of the hematopoietic stem cells or hematopoietic progenitor cells, expression of the interferon-alpha occurs.