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US 9,789,139 B2Granted
Gene therapy vectors for adrenoleukodystrophy and adrenomyeloneuropathy
Assigneebluebird bio, Inc.
InventorsMaria Joann Denaro, Mitchell Howard Finer, Gabor Veres, Julian Down
Life of this patent
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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.
Claims14
A method of gene therapy comprising intravenously administering to a subject having adrenoleukodystrophy or adrenomyeloneuropathy, one or more CD34+ hematopoietic stem or progenitor cells comprising a vector selected from the group consisting of:
- a) a vector comprising from 5′ to 3′:
- (i) a left (5′) retroviral LTR;
- (ii) a central polypurine tract/DNA flap (cPPT/FLAP);
- (iii) a retroviral export element;
- (iv) 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
- (v) a right (3′) retroviral LTR;
- wherein the vector does not comprise a post-transcriptional regulatory element;
- b) a lentiviral vector comprising from 5′ to 3′:
- (i) a left (5′) LTR;
- (ii) a cPPT/FLAP;
- (iii) an RRE;
- (iv) a MND promoter operably linked to a polynucleotide encoding a human ABCD1 polypeptide;
- (v) a right (3′) LTR;
- and
- (vi) a polyadenylation sequence;
- wherein the vector does not comprise a post-transcriptional regulatory element;
- c) a lentiviral vector comprising from 5′ to 3′:
- (i) a left (5′) HIV-1 LTR;
- (ii) a Psi (Ψ) packaging signal;
- (iii) a cPPT/FLAP;
- (iv) an RRE;
- (v) a MND promoter, operably linked to a cDNA encoding a human ABCD1 polypeptide;
- (vi) a right (3′) self-inactivating (SIN) HIV-1 LTR;
- and
- (vii) a rabbit β-globin polyadenylation sequence;
- wherein the vector does not comprise a post-transcriptional regulatory element;
- d) a vector comprising from 5′ to 3′:
- (i) a left (5′) retroviral LTR;
- (ii) a central polypurine tract/DNA flap (cPPT/FLAP);
- (iii) a retroviral export element;
- (iv) a promoter active in a microglial cell, operably linked to a polynucleotide encoding an ATP-binding cassette, sub-family D, member 1 (ABCD1) polypeptide;
- (v) a right (3′) retroviral LTR;
- (vi) a polyadenylation (polyA) sequence;
- and
- wherein the vector does not comprise a post-transcriptional regulatory element;
- and
- e) a lentiviral vector comprising from 5′ to 3′:
- (i) a left (5′) HIV-1 LTR;
- (ii) a Psi (Ψ) packaging signal;
- (iii) a cPPT/FLAP;
- (iv) an RRE;
- (v) a MND promoter, operably linked to a cDNA encoding a human ABCD1 polypeptide;
- (vi) a right (3′) self-inactivating (SIN) HIV-1 LTR;
- and
- (vii) a polyadenylation (polyA) sequence;
- wherein the vector does not comprise a post-transcriptional regulatory element;
- wherein the gene therapy treats adrenoleukodystrophy or adrenomyeloneuropathy in the subject.
45 more elements
A method of treating adrenoleukodystrophy or adrenomyeloneuropathy, comprising intravenously administering to a subject one or more CD34+ hematopoietic stem or progenitor cells transduced with a vector selected from the group consisting of:
- a) a vector comprising from 5′ to 3′:
- (i) a left (5′) retroviral LTR;
- (ii) a central polypurine tract/DNA flap (cPPT/FLAP);
- (iii) a retroviral export element;
- (iv) 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
- (v) a right (3′) retroviral LTR;
- wherein the vector does not comprise a post-transcriptional regulatory element;
- b) a lentiviral vector comprising from 5′ to 3′:
- (i) a left (5′) LTR;
- (ii) a cPPT/FLAP;
- (iii) an RRE;
- (iv) a MND promoter operably linked to a polynucleotide encoding a human ABCD1 polypeptide;
- (v) a right (3′) LTR;
- and
- (vi) a polyadenylation sequence;
- wherein the vector does not comprise a post-transcriptional regulatory element;
- c) a lentiviral vector comprising from 5′ to 3′:
- (i) a left (5′) HIV-1 LTR;
- (ii) a Psi (Ψ) packaging signal;
- (iii) a cPPT/FLAP;
- (iv) an RRE;
- (v) a MND promoter, operably linked to a cDNA encoding a human ABCD1 polypeptide;
- (vi) a right (3′) self-inactivating (SIN) HIV-1 LTR;
- and
- (vii) a rabbit β-globin polyadenylation sequence;
- wherein the vector does not comprise a post-transcriptional regulatory element;
- d) a vector comprising from 5′ to 3′:
- (i) a left (5′) retroviral LTR;
- (ii) a central polypurine tract/DNA flap (cPPT/FLAP);
- (iii) a retroviral export element;
- (iv) a promoter active in a microglial cell, operably linked to a polynucleotide encoding an ATP-binding cassette, sub-family D, member 1 (ABCD1) polypeptide;
- (v) a right (3′) retroviral LTR;
- (vi) a polyadenylation (polyA) sequence;
- and
- wherein the vector does not comprise a post-transcriptional regulatory element;
- and
- e) a lentiviral vector comprising from 5′ to 3′:
- (i) a left (5′) HIV-1 LTR;
- (ii) a Psi (Ψ) packaging signal;
- (iii) a cPPT/FLAP;
- (iv) an RRE;
- (v) a MND promoter, operably linked to a cDNA encoding a human ABCD1 polypeptide;
- (vi) a right (3′) self-inactivating (SIN) HIV-1 LTR;
- and
- (vii) a polyadenylation (polyA) sequence;
- wherein the vector does not comprise a post-transcriptional regulatory element;
- wherein the treatment reduces or ameliorates of symptoms of adrenoleukodystrophy or adrenomyeloneuropathy in the subject, or the delays progression of adrenoleukodystrophy or adrenomyeloneuropathy in the subject.
45 more elements
Dependencies are inferred from the claim text.