Gene therapy for treating phenylketonuria
AssigneeThe Trustees of the University of Pennsylvania
InventorsJames M. Wilson, Jenny Agnes Sidrane, Scott Ashley
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Abstract
Compositions and regimens useful in treating phenylketonuria are provided. The compositions include recombinant adeno-associated virus (rAAV) with a transthyretin enhancer and promoter driving expression of a human phenylalanine hydroxylase.
Claims28
A recombinant adeno-associated virus (AAV) comprising an AAV capsid and a vector genome packaged therein, said vector genome comprising:
- a. an AAV 5′ inverted terminal repeat (ITR) sequence;
- b. two copies of an α1-microglogubulin/bikunin precursor enhancer sequence;
- c. a promoter sequence;
- d. a nucleic acid sequence encoding a human phenylalanine hydroxylase (PAH);
- and
- e. an AAV 3′ ITR sequence;
- wherein the nucleic acid sequence encoding human PAH is operably linked to two copies of the α1-microglogubulin/bikunin precursor enhancer sequence.
An aqueous suspension suitable for administration to a phenylketonuria patient, said suspension comprising an aqueous suspending liquid and about 1×1012 genome copies (GC)/mL to about 1×1014 GC/mL of a recombinant adeno-associated virus (AAV) useful as a liver-directed therapeutic for phenylketonuria, said recombinant AAV having an AAV capsid, and having packaged therein a vector genome comprising:
- a. an AAV 5′ inverted terminal repeat (ITR) sequence;
- b. two copies of an al-microglogubulin/bikunin precursor enhancer sequence;
- c. a promoter sequence;
- d. a nucleic acid sequence encoding a human phenylalanine hydroxylase (PAH);
- and
- e. an AAV 3′ ITR sequence;
- wherein the nucleic acid sequence encoding a human PAH is operably linked to two copies of the α1-microglogubulin/bikunin precursor enhancer sequence.
A plasmid comprising an expression cassette, the expression cassette comprising two copies of an al-microglogubulin/bikunin precursor enhancer sequence, a TBG promoter sequence, a nucleic acid sequence encoding a human phenylalanine hydroxylase (PAH), and a bGH polyA sequence, wherein the TBG promoter sequence, codon optimized sequence encoding a human phenylalanine hydroxylase (PAH), and bGH polyA sequence are operably linked.
Dependencies are inferred from the claim text.