Treatment of mucopolysaccharidosis IVA
Inventors
Tomatsu, Shunji • SAWAMOTO, Kazuki • Karumuthil-Melethil, Subha • Danos, Olivier
Assignees
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Publication Number
US-12247213-B2
Publication Date
2025-03-11
Expiration Date
Abstract
Provided herein are gene therapy methods for the treatment of mucopolysaccharidosis type IVA (MPS IVA) 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.
Core Innovation
A recombinant adeno-associated virus (rAAV) is provided that comprises an AAV capsid and a recombinant AAV genome flanked by AAV-inverted terminal repeats (ITRs). The recombinant AAV genome includes a human N-acetylgalactosamine-6-sulfate sulfatase (hGALNS) expression cassette with a promoter operably linked to a nucleotide sequence encoding hGALNS, wherein the promoter is a liver-specific promoter or a liver- and muscle-specific promoter.
The hGALNS nucleotide sequence in the cassette is constrained by sequence identity relative to SEQ ID NO: 16, including at least 80% identity, at least 85% identity, at least 90% identity, at least 95% identity, at least 98% identity, or 100% identity. The document further describes hGALNS encoded as a fusion protein with an acidic oligopeptide D8, with the fusion described as designed to produce mannose-6-phosphate glycosylated enzyme in connection with liver-derived expression and secretion.
The described approach is directed to gene-therapy treatment of mucopolysaccharidosis type IVA (MPS IVA, Morquio A syndrome). The patent document states that the fusion and liver expression lead to mannose-6-phosphate glycosylated hGALNS enabling cross-correction to bone/cartilage and other organs, supported by maintained supraphysiological circulating hGALNS activity and reductions or normalization of plasma mono-sulfated KS.
Claims Coverage
The independent claim coverage centers on an rAAV defined by an AAV capsid plus an AAV genome with an hGALNS expression cassette flanked by ITRs, using a liver-specific or liver- and muscle-specific promoter and a nucleotide sequence meeting defined identity thresholds relative to SEQ ID NO: 16. Additional features include at least five further inventive constraints across dependent claims.
rAAV with AAV capsid and ITR-flanked hGALNS expression cassette
An rAAV comprising an AAV capsid and a recombinant AAV genome flanked by AAV-inverted terminal repeats (ITRs), wherein the recombinant AAV genome comprises a human hGALNS expression cassette.
Liver-specific or liver- and muscle-specific promoter for hGALNS cassette
The hGALNS expression cassette comprises a promoter operably linked to a nucleotide sequence encoding hGALNS, wherein the promoter is a liver-specific promoter or a liver- and muscle-specific promoter.
hGALNS nucleotide sequence identity relative to SEQ ID NO: 16
The hGALNS expression cassette includes a nucleotide sequence that comprises at least 80% identical to SEQ ID NO: 16, or at least 85% identical to SEQ ID NO: 16, or at least 90% identical to SEQ ID NO: 16, or at least 95% identical to SEQ ID NO: 16, or at least 98% identical to SEQ ID NO: 16, or 100% identical to SEQ ID NO: 16.
AAV capsid subtype as AAV8
The rAAV is characterized by using AAV8 as the AAV type.
CpG site depletion in transgene
The recombinant AAV is characterized by a transgene nucleotide sequence with depleted CpG sites.
hGALNS fusion with acidic oligopeptide and identity constraints to SEQ ID NO: 3/SEQ ID NO: 5
The rAAV provides an hGALNS expression cassette where hGALNS is encoded as a fusion with an acidic oligopeptide, and includes hGALNS or the hGALNS portion sequences matching SEQ ID NO: 3 or encoding a fusion protein sequence matching SEQ ID NO: 5, with high identity thresholds.
Treatment of MPS IVA with mannose-6-phosphate glycosylated hGALNS produced and secreted from liver cells
Treating a human subject diagnosed with MPS IVA by delivering to multiple specified tissues or organs a therapeutically effective amount of hGALNS that is produced from an rAAV genome and glycosylated with mannose-6-phosphate via production and secretion from a liver cell.
Overall, the claims coverage centers on an rAAV vector carrying an ITR-flanked human hGALNS expression cassette driven by a liver-specific or liver- and muscle-specific promoter, with defined nucleotide sequence identity requirements to SEQ ID NO: 16. The dependent coverage further narrows the capsid to AAV8, includes transgene CpG depletion, and specifies additional sequence and fusion characteristics involving SEQ ID NO: 3 and SEQ ID NO: 5, as well as an MPS IVA treatment context involving mannose-6-phosphate glycosylated hGALNS produced and secreted from liver cells.
Stated Advantages
Maintained supraphysiological circulating hGALNS activity.
Reduction or normalization of plasma mono-sulfated KS.
Improved histopathology of bone and cartilage, including growth plate, articular cartilage, meniscus, and ligament.
Clearance of heart valve and heart muscle pathology in MPS IVA mouse models.
Designed to enable cross-correction to bone/cartilage and other organs via mannose-6-phosphate glycosylated enzyme.
Restoration of plasma hGALNS enzyme activity after about 2 weeks following intravenous administration.
D8 provides higher early plasma hGALNS activity and prolonged circulating activity.
Cross-correction with detectable enzyme activity across multiple tissues including spleen, lung, kidney, bone, and heart.
Normalization or major reduction of mono-sulfated keratan sulfate (mono-sulfated KS; mono-KS) levels in plasma and tissues.
Improved bone and cartilage pathology including growth plate, articular cartilage, ligaments, and meniscus.
Near-complete clearance in heart lesions.
Documented Applications
Gene-therapy treatment of mucopolysaccharidosis type IVA (MPS IVA, Morquio A syndrome) in a human subject diagnosed with MPS IVA, with delivery to multiple specified tissues or organs of a therapeutically effective amount of hGALNS produced from an rAAV genome and glycosylated with mannose-6-phosphate via liver-cell production and secretion.
Treatment context in MPS IVA mouse models including KO and immune-tolerant MTOL, with reported clearance of heart valve and heart muscle pathology and improved histopathology in bone and cartilage.
Therapeutic evaluation and treatment context in MPS IVA mouse models including Galns KO and MTOL with intravenous administration of AAV8-TBG-hGALNSco and AAV8-TBG-D8-hGALNSco, measuring plasma and liver hGALNS activity, tissue enzyme activity, mono-sulfated KS levels, and histopathology.
Treating a human subject diagnosed with MPS IVA by delivering a therapeutically effective amount of hGALNS to multiple specified tissues or organs.
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