DNA sequences encoding dystrophin minigenes and methods of use thereof
AssigneeAsklepios Biopharmaceutical, Inc.
InventorXiao Xiao
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Abstract
The present invention provides a series of novel dystrophin minigenes that retain the essential biological functions. The expression of the dystrophin minigenes may be controlled by a regulatory element along with a small polyadenylation signal. The entire gene expression cassettes may be readily packaged into a viral vector, preferably an AAV vector. The present invention further defines the minimal functional domains of dystrophin and provides ways to optimize and create new versions of dystrophin minigenes. Finally, the present invention provides a method of treatment for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).
Claims28
An isolated nucleotide sequence encoding a dystrophin minigene comprising:
- (a) a N-terminal domain;
- (b) four to six rod repeats;
- (c) an HI domain of a dystrophin gene and an H4 domain of the dystrophin gene;
- and
- (d) a cysteine-rich domain,
- wherein the N-terminal domain is selected from a group consisting of a N-terminal domain of the dystrophin gene, a modified N-terminal domain of the dystrophin gene, and a N-terminal domain of a utrophin gene;
- the rod repeats are selected from a group consisting of rod repeats in the dystrophin gene, rod repeats in the utrophin gene, and rod repeats in a spectrin gene;
- the cysteine-rich domain is a cysteine-rich domain of the dystrophin gene or a cysteine-rich domain of the utrophin gene.
An isolated nucleotide sequence encoding a dystrophin minigene comprising:
- (a) a N-terminal domain of a dystrophin gene or a modified N-terminal domain of the dystrophin gene;
- (b) four to six rod repeats of the dystrophin gene;
- (c) an H1 domain of the dystrophin gene and an H4 domain of the dystrophin gene;
- and
- (d) a cysteine-rich domain of the dystrophin gene,
- wherein said nucleotide sequence has fewer than 5,000 nucleotides.
A method of treating Duchenne muscular dystrophy and Becker muscular dystrophy in a mammalian subject, comprising:
- (i) providing a vector comprising a dystrophin minigene operably linked to an expression control element;
- (ii) administering an effective amount of said vector to the mammalian subject under conditions that result in the expression of the dystrophin minigene at a level that provides a therapeutic effect in said mammalian subject,
- wherein the dystrophin minigene has fewer than 5,000 nucleotides comprising:
- (a) a N-terminal domain of a dystrophin gene or a modified N-terminal domain of the dystrophin gene;
- (b) four to six rod repeats of the dystrophin gene;
- (c) an H1 domain of a dystrophin gene and an H4 domain of the dystrophin gene;
- and
- (d) a cysteine-rich domain of the dystrophin gene.
Dependencies are inferred from the claim text.