Methods and compositions for the treatment of fabry disease
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Publication Number
US-12758654-B2
Publication Date
2026-10-13
Expiration Date
Abstract
Nucleases and methods of using these nucleases for inserting a sequence encoding a therapeutic α-Gal A protein such as an enzyme into a cell, thereby providing proteins or cell therapeutics for treatment and/or prevention of Fabry disease.
Core Innovation
The patent describes an adeno-associated virus (AAV) expression construct comprising an apolipoprotein E (APOE) enhancer operably linked to an alpha 1-antitrypsin (hAAT) promoter, a human hemoglobin beta-IGG (HBB-IGG) intron, and a cDNA transgene encoding at least one alpha galactosidase A (α-Gal A) protein. Other recited claim elements include a sequence encoding an α-Gal A signal peptide and a bovine growth hormone poly A signal sequence. A pharmaceutical composition further includes a pharmaceutically acceptable carrier or excipient.
The reported figures and summary show sustained α-Gal A activity in plasma and tissues after AAV transduction, with activity varying by α-Gal A variant, dose, and tissue. Reduced Gb3 and lyso-Gb3 levels are reported in treated GLAKO mice, and targeted integration at the albumin locus also produces sustained activity with secreted α-Gal A in secondary tissues. The background section is not included, so the problem being solved is not explicitly described in the patent.
Claims Coverage
The claims contain three independent claims (claims 1, 6, and 12), which define three inventive features. Claim 9 refers to claim 6 and adds a poly A signal sequence, so it is treated as a dependent claim rather than a fourth independent claim.
Pharmaceutical composition containing an AAV expression construct
Claim 1 recites a pharmaceutical composition comprising an AAV expression construct with an APOE enhancer operably linked to an hAAT promoter, an HBB-IGG intron, and a cDNA transgene encoding at least one α-Gal A protein, together with a pharmaceutically acceptable carrier or excipient. Dependent claims specify signal-peptide and poly A signal features, transgene sequence variants, expression in a subject, and a decrease in glycospingolipids.
AAV expression construct encoding α-Gal A
Claim 6 recites an AAV expression construct comprising an APOE enhancer operably linked to an hAAT promoter, an HBB-IGG intron, and a cDNA transgene encoding at least one α-Gal A protein. Dependent claims add a signal-peptide-encoding sequence and a poly A signal sequence (claim 9), including a bovine growth hormone poly A signal sequence, and specify transgene sequence forms, expression in a subject, and a decrease in glycospingolipids.
AAV expression construct with signal peptide and bovine growth hormone poly A signal sequence
Claim 12 recites an AAV expression construct comprising an APOE enhancer linked to an hAAT promoter, an HBB-IGG intron, a sequence encoding an α-Gal A signal peptide, a cDNA transgene encoding at least one α-Gal A protein, and a bovine growth hormone poly A signal sequence. A dependent claim specifies a codon-optimized α-Gal A sequence.
The independent claims cover a pharmaceutical composition and AAV expression constructs that combine the APOE enhancer, hAAT promoter, HBB-IGG intron, and α-Gal A transgene claim elements. The more fully specified construct also includes an α-Gal A signal peptide and a bovine growth hormone poly A signal sequence, with dependent claims reciting certain transgene variants.
Stated Advantages
The figures report sustained α-Gal A activity in plasma and tissues after AAV transduction, with dose-dependent activity; several construct variants reach or exceed wild-type reference activity.
The figures report reduced Gb3 and lyso-Gb3 substrate levels in treated GLAKO mice.
The claims state that the expressed α-Gal A protein decreases glycospingolipids in a subject by at least two-fold.
Targeted integration at the albumin locus produces sustained activity, with secreted α-Gal A detected in secondary tissues.
Documented Applications
AAV-mediated α-Gal A expression for Fabry disease, with the construct, including in the form of a pharmaceutical composition, capable of expressing α-Gal A from its transgene in a subject in need thereof.
AAV transduction and cDNA treatment experiments in GLAKO and Fabry-disease mouse models, with α-Gal A activity reported in plasma and tissues and Gb3 and lyso-Gb3 substrate levels assessed.
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