Treatment of mucopolysaccharidosis iva
AssigneeREGENXBIO Inc.
InventorsDevin MCDOUGALD, Subha KARUMUTHIL-MELETHIL
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Abstract
Provided herein are gene therapy methods for the treatment of mucopolysaccharidosis type IV A (MPS IV A) involving the use of recombinant adeno-associated viruses (rAAVs) to deliver human N-acetylgalactosamine-6-sulfate sulfatase (hGALNS) to the bone of a human subject diagnosed with MPS IVA. Also provided herein are rAAVs that can be used in the gene therapy methods and methods of making such rAAVs.
Claims129
A recombinant adeno-associated virus (rAAV) comprising:
- (a) an AAV capsid;
- and
- (b) a recombinant AAV genome comprising a human N-acetylgalactosamine-6-sulfate sulfatase (hGALNS) expression cassette flanked by AAV-inverted terminal repeats (ITRs), the hGALNS expression cassette comprising a nucleotide sequence encoding a bone-liver tandem promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes hGALNS, wherein the bone-liver tandem promoter comprises a bone-specific promoter and a liver-specific promoter, and wherein the nucleotide sequence encoding the bone-liver tandem promoter is operably linked to the nucleotide sequence encoding the transgene.
An rAAV comprising:
- (a) an AAV capsid;
- and
- (b) a recombinant AAV genome comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a bone-liver tandem promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes a fusion protein that is hGALNS fused to an acidic oligopeptide, wherein the bone-liver tandem promoter comprises a bone-specific promoter and a liver-specific promoter, and wherein the nucleotide sequence encoding the bone-liver tandem promoter is operably linked to the nucleotide sequence encoding the transgene.
An rAAV comprising:
- (a) an AAV capsid;
- and
- (b) a recombinant AAV genome comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a Sp7/Osx promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes hGALNS, and wherein the nucleotide sequence encoding the Sp7/Osx promoter is operably linked to the nucleotide sequence encoding the transgene.
An rAAV comprising:
- (a) an AAV capsid;
- and
- (b) a recombinant AAV genome comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a Sp7/Osx promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes a fusion protein that is hGALNS fused to an acidic oligopeptide, and wherein the nucleotide sequence encoding the Sp7/Osx promoter is operably linked to the nucleotide sequence encoding the transgene.
An rAAV comprising:
- (a) an AAV capsid;
- and
- (b) a recombinant AAV genome comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a minimal Sp7/Osx promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes hGALNS, and wherein the nucleotide sequence encoding the minimal Sp7/Osx promoter is operably linked to the nucleotide sequence encoding the transgene.
An rAAV comprising:
- (a) an AAV capsid;
- and
- (b) a recombinant AAV genome comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a minimal Sp7/Osx promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes a fusion protein that is hGALNS fused to an acidic oligopeptide, and wherein the nucleotide sequence encoding the minimal Sp7/Osx promoter is operably linked to the nucleotide sequence encoding the transgene.
A polynucleotide comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a bone-liver tandem promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes hGALNS, wherein the bone-liver tandem promoter comprises a bone-specific promoter and a liver-specific promoter, and wherein the nucleotide sequence encoding the bone-liver tandem promoter is operably linked to the nucleotide sequence encoding the transgene.
A polynucleotide comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a bone-liver tandem promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes a fusion protein that is hGALNS fused to an acidic oligopeptide, wherein the bone-liver tandem promoter comprises a bone-specific promoter and a liver-specific promoter, and wherein the nucleotide sequence encoding the bone-liver tandem promoter is operably linked to the nucleotide sequence encoding the transgene.
A polynucleotide comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a Sp7/Osx promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes hGALNS, and wherein the nucleotide sequence encoding the Sp7/Osx promoter is operably linked to the nucleotide sequence encoding the transgene.
A polynucleotide comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a Sp7/Osx promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes a fusion protein that is hGALNS fused to an acidic oligopeptide, and wherein the nucleotide sequence encoding the Sp7/Osx promoter is operably linked to the nucleotide sequence encoding the transgene.
A polynucleotide comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a minimal Sp7/Osx promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes hGALNS, and wherein the nucleotide sequence encoding the minimal Sp7/Osx promoter is operably linked to the nucleotide sequence encoding the transgene.
A polynucleotide comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a minimal Sp7/Osx promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes a fusion protein that is hGALNS fused to an acidic oligopeptide, and wherein the nucleotide sequence encoding the minimal Sp7/Osx promoter is operably linked to the nucleotide sequence encoding the transgene.
An rAAV comprising:
- (a) an AAV capsid;
- and
- (b) a recombinant AAV genome comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a promoter and a nucleotide sequence encoding a transgene, wherein the transgene encodes hGALNS, wherein the nucleotide sequence encoding the promoter is operably linked to the nucleotide sequence encoding the transgene, and wherein the nucleotide sequence encoding the transgene comprises:
- (a) a nucleotide sequence that is at least 80% identical to SEQ ID NO:
- 27;
- (b) a nucleotide sequence that is at least 85% identical to SEQ ID NO:
- 27;
- (c) a nucleotide sequence that is at least 90% identical to SEQ ID NO:
- 27;
- (d) a nucleotide sequence that is at least 95% identical to SEQ ID NO:
- 27;
- (e) a nucleotide sequence that is at least 98% identical to SEQ ID NO:
- 27;
- or
- (f) a nucleotide sequence that is 100% identical to SEQ ID NO:
- 27.
A polynucleotide comprising an hGALNS expression cassette flanked by AAV-ITRs, the hGALNS expression cassette comprising a nucleotide sequence encoding a promoter and a nucleotide sequence encoding a transgene, and wherein the nucleotide sequence encoding the promoter is operably linked to the nucleotide sequence encoding the transgene.
The rAAV of any one of claim 113-115 or 123 or the polynucletide of any one of claim 116 or 124, wherein the nucleotide sequence encoding the promoter comprises:
- (a) a nucleotide sequence that is at least 80% identical to SEQ ID NO:
- 16;
- (b) a nucleotide sequence that is at least 85% identical to SEQ ID NO:
- 16;
- (c) a nucleotide sequence that is at least 90% identical to SEQ ID NO:
- 16;
- (d) a nucleotide sequence that is at least 95% identical to SEQ ID NO:
- 16;
- (e) a nucleotide sequence that is at least 98% identical to SEQ ID NO:
- 16;
- or
- (f) a nucleotide sequence that is 100% identical to SEQ ID NO:
- 16.
Dependencies are inferred from the claim text.