Development of novel gene therapeutics for fibrodysplasia ossificans progressiva
AssigneeUniversity of Massachusetts
InventorsJae-Hyuck Shim, Guangping Gao, Jun Xie, Yeon-Suk Yang, Jung Min Kim, Sachin Chaugule
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Abstract
In some aspects, the disclosure relates to compositions and methods for treating fibrodysplasia ossificans progressiva (FOP) in a subject. In some aspects, the disclosure provides isolated nucleic acids, and vectors such as rAAV vectors, configured to express transgenes that inhibit (e.g., decrease) expression of mutated AVCR1 gene in muscle cells or connective tissues.
Claims30
A recombinant adeno-associated virus (rAAV) comprising:
- (i) an isolated nucleic acid comprising a transgene comprising a promoter operably linked to a codon optimized nucleic acid sequence encoding an ACVR1;
- and
- (ii) at least one AAV capsid protein.
A recombinant adeno-associated virus (rAAV) comprising:
- (i) at least one AAV capsid protein;
- and
- (ii) a nucleic acid that encodes an artificial miRNA (ami-RNA) comprising a nucleic acid having sufficient sequence complementary with an endogenous mRNA of a subject to hybridize with and inhibit expression of the endogenous mRNA, wherein the endogenous mRNA encodes an ACVR1 protein;
- and/or
- (iii) a nucleic acid that encodes a transgene comprising a codon optimized nucleic acid sequence encoding an ACVR1.
A recombinant gene editing complex comprising:
- (i) a single guide RNA (sgRNA) that specifically hybridizes to a target nucleic acid sequence of an ACVR1 gene;
- (ii) a first rAAV particle encoding a first recombinant gene editing protein or fragment thereof;
- and
- (iii) a second rAAV particle encoding a second recombinant gene editing protein or fragment thereof.
The recombinant gene editing complex of 17, wherein the recombinant gene editing protein is a protein of the Crisper/Cas9 system.
The recombinant gene editing complex of 17, wherein the rAAV particles comprises an AAV9 capsid protein or variant thereof or an AAV6.2 capsid protein or variant thereof.
A method of treating a subject having or suspected of having fibrodysplasia ossificans progressiva (FOP), the method comprising administering to the subject the rAAV of:
- (i) at least one AAV capsid protein;
- and
- (ii) a nucleic acid that encodes an artificial miRNA (ami-RNA) comprising a nucleic acid having sufficient sequence complementary with an endogenous mRNA of a subject to hybridize with and inhibit expression of the endogenous mRNA, wherein the endogenous mRNA encodes an ACVR1 protein;
- and/or
- (iii) a nucleic acid that encodes a transgene comprising a codon optimized nucleic acid sequence encoding an ACVR1.
Dependencies are inferred from the claim text.