Compositions useful in treatment of ornithine transcarbamylase (OTC) deficiency
AssigneeThe Trustees of the University of Pennsylvania
InventorsLili Wang, James M. Wilson
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Abstract
Viral vectors comprising engineered hOTC DNA and RNA sequences are provided which when delivered to a subject in need thereof are useful for treating hyperammonemia, ornithine transcarbamylase deficiency and symptoms associated therewith. Also provided are methods of using hOTC for treatment of liver fibrosis and/or cirrhosis in OTCD patients by administering hOTC.
Claims23
A nucleic acid molecule comprising a sequence encoding a functional human ornithine transcarbamylase (hOTC) protein,
- wherein the sequence is less than 80% identical to the wild-type hOTC sequence of SEQ ID NO:
- 1, and
- wherein said sequence is selected from a nucleic acid sequence comprising SEQ ID NO:
- 5 or a nucleic acid sequence at least 96% identical thereto.
A plasmid containing an expression cassette comprising:
- an AAV 5′ inverted terminal repeat (ITR),
- an hOTC nucleic acid sequence,
- expression control sequences,
- and an AAV 3′ ITR,
- wherein the hOTC nucleic acid sequence encodes a functional hOTC protein and is less than 80% identical to the wild-type hOTC sequence of SEQ ID NO:
- 1, and
- wherein said hOTC nucleic acid sequence is selected from a nucleic acid sequence comprising SEQ ID NO:
- 5 or a nucleic acid sequence at least 96% identical thereto.
A plasmid comprising a vector genome which comprises
- an AAV2 3′ ITR,
- an AAV2 5′ ITR in which the D-sequence and terminal resolution site (trs) are deleted,
- a thyroxin-binding globulin (TBG) promoter sequence,
- an hOTC coding sequence comprising SEQ ID NO:
- 5, and
- an SV40 polyA sequence.
A plasmid containing an expression cassette comprising:
- an AAV 5′ ITR,
- a nucleic acid sequence that encodes a chimeric ornithine transcarbamylase comprising a mature hOTC protein and a heterologous transit peptide,
- expression control sequences,
- and an AAV 3′ ITR,
- wherein the mature hOTC protein is encoded by a sequence less than 80% identical to the wild-type mature hOTC coding sequence of SEQ ID NO:
- 1, and
- wherein the mature hOTC protein is encoded by a nucleic acid sequence comprising the mature hOTC coding sequence of SEQ ID NO:
- 5 or a nucleic acid sequence at least 96% identical thereto.
Dependencies are inferred from the claim text.