Methods and compositions for the treatment of lysosomal storage diseases
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Publication Number
US-11898158-B2
Publication Date
2024-02-13
Expiration Date
Abstract
Nucleases and methods of using these nucleases for inserting a sequence encoding a therapeutic protein such as an enzyme into a cell, thereby providing proteins or cell therapeutics for treatment and/or prevention of a lysosomal storage disease.
Core Innovation
The document discloses a method of treating a mouse or human with Gaucher's, Fabry's, or Pompe's disease by intravenously injecting multiple AAV vectors encoding a pair of zinc finger nucleases that cleave in an endogenous albumin gene. The approach places disease-specific lysosomal enzyme transgenes into the endogenous albumin gene so that integration occurs in liver cells. The liver cells then express and secrete therapeutic amounts of the protein, and a symptom of the disease is treated.
The method defines a transgene architecture in which the transgene is flanked by sequences having homology with the endogenous albumin gene. The disease-specific transgenes include a glucocerebrosidase (GBA) protein for Gaucher's disease, an α galactosidase deficiency (GLA) protein for Fabry's disease, and an alpha-glucosidase (GAA) protein for Pompe's disease. This design constrains the therapeutic protein to be produced from the albumin-targeted genomic locus in liver cells.
The document further specifies that the first, second, and third AAV vectors are delivered at a ratio of 1:1:8. It also describes that the transgene is integrated into the endogenous albumin gene in liver cells of the mouse or human, and that liver expression and secretion are linked to treating disease symptoms. Additional disclosures address detection and localization of the protein in secondary tissues, including spleen, blood/plasma, kidney, and lung.
Claims Coverage
The partial content contains one independent claim, with dependent claims that further specify disease manifestations, expression control, vector serotypes, detection in secondary tissues, and additional secondary tissue locations. The inventive features are centered on albumin-gene-targeted ZFN-driven integration of disease-specific lysosomal enzyme transgenes delivered by multiple AAV vectors.
Albumin gene-cleaving zinc finger nucleases delivered by AAV
Intravenously injecting first and second AAV vectors encoding first and second ZFNs of a pair of zinc finger nucleases that cleave in an endogenous albumin gene into a mouse or human with Gaucher's, Fabry's, or Pompe's disease.
Disease-specific lysosomal enzyme transgene flanked by albumin homology
Intravenously injecting a third AAV vector comprising a transgene encoding a glucocerebrosidase (GBA) protein for Gaucher's disease, an α galactosidase deficiency (GLA) protein for Fabry's disease, or an alpha-glucosidase (GAA) protein for Pompe's disease, wherein the transgene is flanked by sequences having homology with the endogenous albumin gene.
Albumin-gene integration in liver cells with therapeutic protein secretion at 1:1:8 AAV ratio
Delivering the first, second and third AAV vectors at a ratio of 1:1:8 such that the transgene is integrated into the endogenous albumin gene in liver cells of the mouse or human, wherein the liver cells express and secrete therapeutic amounts of the protein and a symptom of the Gaucher's, Fabry's, or Pompe's disease is treated.
Endogenous albumin promoter-driven expression of the transgene
Expression of the transgene is driven by an endogenous albumin promoter.
AAV2 and/or AAV6 vector use
Using AAV2 and/or AAV6 vectors for delivery.
Detection of the protein in secondary tissues
Detecting the protein in secondary tissues of a mouse or human subject.
Secondary tissue location kidney or lung
Wherein the secondary tissue is kidney or lung.
Overall, the claim set centers on intravenously delivered, albumin-gene-cleaving ZFNs and a disease-specific lysosomal enzyme transgene flanked by endogenous albumin homology, integrated in liver cells to drive expression and secretion and treat disease symptoms, with further dependent limitations on expression control, vector serotypes, protein detection in secondary tissues, and specified secondary tissue locations.
Stated Advantages
Enables integration of therapeutic lysosomal enzyme transgenes into the endogenous albumin gene in liver cells.
Liver cells express and secrete therapeutic amounts of the protein.
Treats a symptom of Gaucher's, Fabry's, or Pompe's disease.
Allows detection of the protein in secondary tissues, including kidney or lung, as specified.
Documented Applications
Treating Gaucher's, Fabry's, or Pompe's disease in a mouse or human by integrating a disease-specific lysosomal enzyme transgene into the endogenous albumin gene in liver cells for therapeutic protein secretion and symptom treatment.
Detecting the protein in secondary tissues of a mouse or human subject, including kidney or lung as specified in dependent disclosures.
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