Use of lentivector-transduced T-Rapa cells for amelioration of lysosomal storage disorders
Inventors
Medin, Jeffrey A. • Fowler, Daniel H. • Nagree, Murtaza S. • Felizardo, Tania
Assignees
Publication Number
US-12239693-B2
Publication Date
2025-03-04
Expiration Date
2039-04-29
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Abstract
The present disclosure provides methods of treating lysosomal storage disorders, e.g., Fabry disease, Gaucher disease, Farber disease, and Pompe disease. The method comprises producing vector-transduced T-Rapa cells that express a transgene of interest and administering the cells to a patient in need thereof. The T-Rapa cells may be transduced with a dual promoter lentivirus vector.
Core Innovation
The invention provides methods for treating lysosomal storage disorders such as Fabry disease, Gaucher disease, Farber disease, and Pompe disease. This is accomplished by producing vector-transduced T-Rapa cells that express a relevant transgene and administering these cells to a patient in need. T-Rapa cells are generated by conditioning T-cells from the patient or a donor with rapamycin ex vivo, and these cells are then transduced in vitro with a vector carrying the gene encoding the enzyme deficient in the specific disorder.
The method addresses limitations associated with prior approaches using hematopoietic stem cells (HSCs), which require intensive conditioning (ablation) and have restricted availability and engraftment issues. By utilizing T-cells, which are easier to obtain from peripheral blood and can be expanded in culture, the approach seeks to provide a renewable, accessible source of therapeutic cells. These gene-modified T-Rapa cells can secrete the therapeutic enzyme and potentially allow for repeated dosing with minimal or no ablation.
The transduced T-Rapa cells may be administered intravenously or by transfusion and can be cryopreserved for future use. The invention also encompasses the use of dual promoter lentiviral vectors that may encode both the therapeutic enzyme and a selectable marker (such as IMPDH2(IY)), enhancing in vivo enrichment of the therapeutic T-Rapa cell population upon administration of a suitable drug (e.g., mycophenolate mofetil).
Claims Coverage
The patent contains one independent claim detailing multiple inventive features for the method of treating Fabry disease using transduced T-Rapa cells.
Ex vivo conditioning of T-cells with rapamycin to generate T-Rapa cells
T-cells from a subject with Fabry disease are conditioned ex vivo with rapamycin to generate T-Rapa cells.
Transduction of T-Rapa cells with enzyme-encoding vector
The T-Rapa cells are transduced in vitro with a vector containing a transgene encoding an enzyme associated with a lysosomal storage disorder, specifically alpha-galactosidase A (α-gal A).
Expansion and intravenous administration of transduced T-Rapa cells
The vector-transduced T-Rapa cells are expanded in vitro and administered back to the subject via intravenous infusion.
Reduction of substrate globotriaosylceramide (Gb3)
The administered T-Rapa cells express the relevant enzyme and reduce the level of globotriaosylceramide (Gb3) in the subject.
The inventive features focus on the process of generating, modifying, expanding, and administering rapamycin-conditioned T-cells transduced with a vector encoding alpha-galactosidase A, providing a cellular therapy to reduce Gb3 in Fabry disease patients.
Stated Advantages
The method reduces the need for myeloid cell depletion, lowering infectious complications associated with myeloid depletion.
Gene therapy can be performed in the outpatient setting, lowering treatment morbidity and cost.
The method allows repetitive dosing of gene therapy, which can improve efficacy.
T-cells are easier to obtain from peripheral blood without mobilization and can be expanded exponentially in culture.
The approach enables production of therapeutic cells requiring minimal or no ablation.
Documented Applications
Treatment of Fabry disease by administering transduced T-Rapa cells expressing alpha-galactosidase A (α-gal A) to patients.
Treatment of Gaucher disease by administering transduced T-Rapa cells expressing beta-glucocerebrosidase (GBA) to patients.
Treatment of Farber disease by administering transduced T-Rapa cells expressing acid ceramidase (ASAH1) to patients.
Treatment of Pompe disease by administering transduced T-Rapa cells expressing acid alpha-glucosidase (GAA) to patients.
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