Adeno-associated virus compositions for restoring F8 gene function and methods of use thereof
AssigneesCity of Hope, Homology Medicines, Inc.
InventorsSaswati Chatterjee, Laura Jane Smith, Jeff Lynn Ellsworth, Hillard Rubin, Jason Boke Wright, James Anthony McSwiggen
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Abstract
Provided herein are adeno-associated virus (AAV) compositions that can restore F8 gene function in a cell without co-transducing or co-administering an exogenous nuclease or a nucleotide sequence that encodes an exogenous nuclease. Also provided are methods of using the AAV compositions to correct an F8 gene mutation and/or treat a disease or disorder associated with an F8 gene mutation. Packaging systems for making the adeno-associated virus compositions are also provided.
Claims18
A method for correcting a mutation in an F8 gene in a cell, the method comprising transducing the cell with a replication-defective adeno-associated virus (AAV) comprising:
- a) an AAV capsid comprising an AAV Clade F capsid protein;
- and
- b) a correction genome comprising from 5′ to 3′:
- (i) a 5′ AAV ITR nucleotide sequence;
- (ii) a 5′ homology arm nucleotide sequence of up to 2000 nucleotides in length, comprising a nucleotide sequence that is at least 99% identical to SEQ ID NO:
- 27;
- (iii) an editing element for editing a target locus in the F8 gene, comprising an F8 nucleotide sequence that encodes an amino acid sequence consisting of the amino acid sequence encoded by SEQ ID NO:
- 26 operably linked to a polyadenylation sequence;
- (iv) a 3′ homology arm nucleotide sequence of up to 2000 nucleotides in length, comprising a nucleotide sequence that is at least 99% identical to SEQ ID NO:
- 28;
- and
- (v) a 3′ AAV ITR nucleotide sequence,
- wherein the cell is transduced without co-transducing or co-administering an exogenous nuclease or a nucleotide sequence that encodes an exogenous nuclease.
A method for treating a subject having a disease or disorder associated with an F8 gene mutation, the method comprising administering to the subject an effective amount of a replication-defective AAV comprising:
- a) an AAV capsid comprising an AAV Clade F capsid protein;
- and
- b) a correction genome comprising from 5′ to 3′:
- (i) a 5′ AAV ITR nucleotide sequence;
- (ii) a 5′ homology arm nucleotide sequence of up to 2000 nucleotides in length, comprising a nucleotide sequence that is at least 99% identical to SEQ ID NO:
- 27;
- (iii) an editing element for editing a target locus in the F8 gene, comprising an F8 nucleotide sequence that encodes an amino acid sequence consisting of the amino acid sequence encoded by SEQ ID NO:
- 26 operably linked to a polyadenylation sequence;
- (iv) a 3′ homology arm nucleotide sequence of up to 2000 nucleotides in length, comprising a nucleotide sequence that is at least 99% identical to SEQ ID NO:
- 28;
- and
- (v) a 3′ AAV ITR nucleotide sequence,
- wherein an exogenous nuclease or a nucleotide sequence that encodes an exogenous nuclease is not co-administered to the subject, optionally wherein the disease or disorder is hemophilia A and optionally wherein the subject is a human subject.
Dependencies are inferred from the claim text.