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US 2024/0191213 A1Published application
Gene therapies for 21-hydroxylase deficiency
OwnerClayton BEARD, Kamal BHARUCHA +7inventors
InventorsClayton BEARD, Kamal BHARUCHA, Pierre BOUGNERES, Eric DAVID, Rachel ECLOV, Rafael ESCANDON, Genevieve LAFORET, Adam SHAYWITZ, Sophie LE FUR
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Abstract
Disclosed herein are recombinant adeno-associated viral vectors expressing 21-hydroxy lase (21OH) protein and related uses for treating 21OH deficiency.
Claims89
A method, comprising:
- administering to a subject a therapeutically effective amount of a recombinant adeno-associated virus (rAAV) vector, wherein the rAAV vector comprises:
- (i) a nucleic acid molecule comprising at least one AAV inverted terminal repeat (ITR) and
- (ii) a non-AAV nucleotide sequence encoding a 21-hydroxylase (21OH) protein, wherein the non-AAV nucleotide sequence is operably linked to a promoter;
- and
- wherein the therapeutically effective amount is in the range of about 1012 vector genomes per kilogram (vg/kg) to about 1014 vg/kg.
2 more elements
A method of expressing 21-hydroxlase (21OH) in a subject in need thereof, comprising:
- administering to the subject a therapeutically effective amount of a recombinant adeno-associated virus (rAAV) vector, wherein the rAAV vector comprises:
- (i) a nucleic acid molecule comprising at least one AAV inverted terminal repeat (ITR) and
- (ii) a non-AAV nucleotide sequence encoding a 21-hydroxylase (21OH) protein, wherein the non-AAV nucleotide sequence is operably linked to a promoter;
- and
- wherein the therapeutically effective amount is in the range of about 1012 vector genomes per kilogram (vg/kg) to about 1014 vg/kg,
- thereby expressing 21OH in the subject.
3 more elements
A method of treating a subject having 21-hydroxylase deficiency (21OHD), comprising:
- administering to the subject a therapeutically effective amount of a recombinant adeno-associated virus (rAAV) vector, wherein the rAAV vector comprises:
- (i) a nucleic acid molecule comprising at least one AAV inverted terminal repeat (ITR) and
- (ii) a non-AAV nucleotide sequence encoding a 21-hydroxylase (21OH) protein, wherein the non-AAV nucleotide sequence is operably linked to a promoter;
- and
- wherein the therapeutically effective amount is in the range of about 1012 vector genomes per kilogram (vg/kg) to about 1014 vg/kg,
- thereby treating 21OHD in the subject.
3 more elements
A method of increasing the level of cortisol and/or aldosterone in a subject in need thereof, comprising:
- administering to the subject a therapeutically effective amount of a recombinant adeno-associated virus (rAAV) vector, wherein the rAAV vector comprises:
- (i) a nucleic acid molecule comprising at least one AAV inverted terminal repeat (ITR) and
- (ii) a non-AAV nucleotide sequence encoding a 21-hydroxylase (21OH) protein, wherein the non-AAV nucleotide sequence is operably linked to a promoter;
- and
- wherein the therapeutically effective amount is in the range of about 1012 vector genomes per kilogram (vg/kg) to about 1014 vg/kg,
- thereby increasing the level of cortisol and/or aldosterone in the subject.
3 more elements
A method of decreasing the level of progesterone, 17-OHP, renin and/or androstenedione (A4) in a subject in need thereof, comprising:
- administering to the subject a therapeutically effective amount of a recombinant adeno-associated virus (rAAV) vector, wherein the rAAV vector comprises:
- (i) a nucleic acid molecule comprising at least one AAV inverted terminal repeat (ITR) and
- (ii) a non-AAV nucleotide sequence encoding a 21-hydroxylase (21OH) protein, wherein the non-AAV nucleotide sequence is operably linked to a promoter;
- and
- wherein the therapeutically effective amount is in the range of about 1012 vector genomes per kilogram (vg/kg) to about 1014 vg/kg,
- thereby decreasing the level of progesterone, 17-OHP, renin and/or androstenedione (A4) in the subject.
3 more elements
A method, comprising:
- administering to a subject about 1012 vector genomes per kilogram (vg/kg) to about 1014 vg/kg of a recombinant adeno-associated virus 5 (rAAV5) vector, wherein the rAAV5 vector comprises:
- (i) a nucleic acid molecule comprising at least one AAV inverted terminal repeat (ITR), and
- (ii) a non-AAV nucleotide sequence encoding the amino acid sequence of SEQ ID NO:
- 1, wherein the non-AAV nucleotide sequence is operably linked to a promoter that directs expression of the 21OH protein in an adrenal gland cell or an adrenal cortex cell.
1 more element
A method of treating a subject having 21-hydroxylase deficiency (21OHD), comprising:
- intravenously administering to the subject about 1.5×1013 vector genomes per kilogram (vg/kg) of a recombinant adeno-associated virus 5 (rAAV5) vector, wherein the rAAV5 vector comprises:
- (i) a nucleic acid molecule comprising at least one AAV inverted terminal repeat (ITR), and
- (ii) a non-AAV nucleotide sequence encoding the amino acid sequence of SEQ ID NO:
- 1, wherein the non-AAV nucleotide sequence is operably linked to a promoter that directs expression of the 21OH protein in an adrenal gland cell or an adrenal cortex cell,
- thereby treating 21OHD in the subject.
2 more elements
A method of treating a subject having 21-hydroxylase deficiency (21OHD), comprising:
- intravenously administering to the subject about 3×1013 vector genomes per kilogram (vg/kg) of a recombinant adeno-associated virus 5 (rAAV5) vector, wherein the rAAV5 vector comprises:
- (i) a nucleic acid molecule comprising at least one AAV inverted terminal repeat (ITR), and
- (ii) a non-AAV nucleotide sequence encoding the amino acid sequence of SEQ ID NO:
- 1, wherein the non-AAV nucleotide sequence is operably linked to a promoter that directs expression of the 21OH protein in an adrenal gland cell or an adrenal cortex cell,
- thereby treating 21OHD in the subject.
2 more elements
A method of treating a subject having 21-hydroxylase deficiency (21OHD), comprising:
- intravenously administering to the subject about 6×1013 vector genomes per kilogram (vg/kg) of a recombinant adeno-associated virus 5 (rAAV5) vector, wherein the rAAV5 vector comprises:
- (i) a nucleic acid molecule comprising at least one AAV inverted terminal repeat (ITR), and
- (ii) a non-AAV nucleotide sequence encoding the amino acid sequence of SEQ ID NO:
- 1, wherein the non-AAV nucleotide sequence is operably linked to a promoter that directs expression of the 21OH protein in an adrenal gland cell or an adrenal cortex cell,
- thereby treating 21OHD in the subject.
2 more elements
A method, comprising:
- administering to the subject a therapeutically effective amount of a recombinant adeno-associated virus 5 (rAAV5) vector and a therapeutically effective amount of an immunosuppressant,
- wherein the rAAV5 comprises a nucleic acid molecule comprising:
- (i) at least one AAV inverted terminal repeat (ITR) and
- (ii) a non-AAV nucleotide sequence encoding the amino acid sequence of SEQ ID NO:
- 1, wherein the non-AAV nucleotide sequence is operably linked to a promoter that directs expression of the 21OH protein in an adrenal gland cell or an adrenal cortex cell.
2 more elements
A method of treating a subject having 21-hydroxylase deficiency (21OHD), comprising:
- intravenously administering to the subject a therapeutically effective amount of a recombinant adeno-associated virus 5 (rAAV5) vector and a therapeutically effective amount of an immunosuppressant,
- wherein the rAAV5 comprises a nucleic acid molecule comprising:
- (i) at least one AAV inverted terminal repeat (ITR) and
- (ii) a non-AAV nucleotide sequence encoding the amino acid sequence of SEQ ID NO:
- 1, wherein the non-AAV nucleotide sequence is operably linked to a promoter that directs expression of the 21OH protein in an adrenal gland cell or an adrenal cortex cell,
- thereby treating 21OHD in the subject.
3 more elements
Dependencies are inferred from the claim text.