Granted Patent
B2
US 12,257,321 · App. 18/150,377 · Granted Mar 25, 2025
Optimized mini-dystrophin genes and expression cassettes and their use
Inventors:
Xiao Xiao (Chapel Hill, NC); Juan Li (Chapel Hill, NC); Chunping Qiao (Chapel Hill, NC); Scott W. J. McPhee (Chapel Hill, NC); Richard J. Samulski (Hillsborough, NC); Maritza McIntyre (Rockville, MD)
A61K48/0058A61K38/1709A61K45/06C07K14/4708C07K14/78C12N15/86A01K2217/075A01K2227/10A01K2227/105A01K2267/0306C12N2750/14143C12N2800/22C12N2830/008
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Abstract
This invention relates to polynucleotides encoding mini-dystrophin proteins, viral vectors comprising the same, and methods of using the same for delivery of mini-dystrophin to a cell or a subject.
Claims (16)
1. A recombinant AAV (rAAV) particle comprising an AAV9 capsid and a vector genome, said genome comprising a first AAV2 inverted terminal repeat (ITR), a muscle-specific transcriptional regulatory element operably linked to a nucleotide sequence encoding a human mini-dystrophin protein consisting of the amino acid sequence of SEQ ID NO: 7, a transcription termination sequence, and a second AAV2 ITR.
2. The rAAV particle of claim 1 , wherein said vector genome is single-stranded DNA.
3. The rAAV particle of claim 1 , wherein said nucleotide sequence encoding human mini-dystrophin protein is codon-optimized.
4. The rAAV particle of claim 3 , wherein codon-optimization increases GC content relative to wild-type coding sequence.
5. The rAAV particle of claim 4 , wherein the GC content of said nucleotide sequence is at least 60%.
6. The rAAV particle of claim 3 , wherein said nucleotide sequence encoding human mini-dystrophin protein is human codon-optimized.
7. The rAAV particle of claim 1 , wherein said muscle-specific transcriptional regulatory element confers muscle tissue-specific expression in skeletal and cardiac muscle.
8. The rAAV particle of claim 7 , wherein said muscle-specific transcriptional regulatory element is a synthetic enhancer and promoter derived from a muscle creatinine kinase gene.
9. The rAAV particle of claim 3 , wherein said nucleotide sequence encoding human mini-dystrophin protein is at least 90% identical to the nucleotide sequence of SEQ ID NO:1.
10. The rAAV particle of claim 9 , wherein said muscle-specific transcriptional regulatory element comprises the nucleotide sequence of SEQ ID NO:16.
11. The rAAV particle of claim 10 , wherein said transcription termination sequence comprises the nucleotide sequence of SEQ ID NO:17.
12. The rAAV particle of claim 11 , wherein said vector genome comprises the nucleotide sequence of SEQ ID NO:18, or the reverse complement thereof.
13. A method of making the rAAV particle of claim 1 , comprising:
introducing into a cell a polynucleotide comprising the nucleotide sequence of said vector genome, a polynucleotide comprising an AAV rep gene, a polynucleotide comprising an AAV9 cap gene and, optionally, a polynucleotide encoding one or more viral helper genes, incubating said cell; and
purifying the rAAV particles produced thereby.
14. A rAAV particle produced by the method of claim 13 .
Continuity (5)
Provisional Application
62516449
· Jun 7, 2017
Provisional Application
62352675
· Jun 21, 2016
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[cited by applicant]