Autologous, lentivirus-modified, T-rapa cell "micropharmacies" for lysosomal storage disorders

Area of Science:

• Cellular therapy
• Gene therapy
• Biochemistry

Background:

• T cells are widely used in cell therapy due to accessibility, expansion, and genetic modification ease.
• Rapamycin conditioning enhances T cell memory, survival, and reduces inflammatory potential for improved engraftment.
• Rapamycin-conditioned T cells have shown safety in clinical settings with fewer infusion-related adverse events.

Purpose of the Study:

• To evaluate ex vivo lentivirus-modified, rapamycin-conditioned CD4+ T cells as cellular delivery vehicles ('micropharmacies') for enzyme replacement in lysosomal storage disorders.
• To assess the therapeutic potential of this platform for Fabry, Gaucher, Farber, and Pompe diseases in vitro and in vivo.

Main Methods:

• T cells were genetically modified ex vivo using lentivirus vectors and conditioned with rapamycin.
• Engineered T cells were evaluated as 'micropharmacies' for enzyme dissemination in vitro and in vivo.
• Therapeutic efficacy was assessed in mouse models for specific lysosomal storage disorders, including Fabry disease.

Main Results:

• Ex vivo modified, rapamycin-conditioned T cells demonstrated potential as cellular delivery vehicles.
• Micropharmacies expressing alpha-galactosidase A for Fabry disease were successfully transplanted in mice.
• Functional enzyme delivery to key tissues (kidney, heart) and pathogenic substrate clearance were observed after a single administration.

Conclusions:

• Rapamycin-conditioned T cells can be engineered into effective 'micropharmacies' for treating lysosomal storage disorders.
• This cell-based enzyme delivery platform shows promise for multiple genetic diseases, including Fabry disease.
• The approach offers a potential next-generation therapeutic strategy with demonstrated in vivo efficacy and safety.