T cells previously programmed to disseminate corrective enzymes delivered in both in vivo and ex vivo tissues act as a possible therapeutic option for Pompe disease (PD) and other lysosomal storage disorders (LSDs), according to a new study published in EMBO Molecular Medicine.

“We provide proof-of-concept for the use of lentivirus-modified rapamycin-conditioned T cells – ‘T-Rapa micropharmacies’ – as a source of autologous enzyme production for LSDs,” the authors said. “We show that T-Rapa micropharmacies can be made from Fabry patient cells and that transplant of these cells into mice results in systemic reduction of pathogenic substrate.”

This experimental study conducted by Nagree et al conditioned CD4+ T cells with rapamycin and later integrated with a lentivirus that promotes the expression of enhanced green fluorescent protein in at least 40% of the cells. This mechanism acts as a transport to introduce lacking enzymes, a system called micropharmacies. In the case of PD, an analogous vector with codon-optimized transgene for the GAA gene responsible for the expression of ⍺-glucosidase was utilized.

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An ex vivo analysis showed that skin fibroblasts successfully increased their ⍺-galactosidase A activity by up to 33% after culturing them with T cell micropharmacies. Afterward, the authors conducted in vivo experiments in mice that lacked ⍺-galactosidase A, and after engraftment with modified T cells “T-Rapa,” the enzyme activity was significantly higher, and plasma levels increased.

While yielding promising results, some concerns are yet to be addressed. For example, safety remains unclear since all mice died at 4 weeks regardless of the treatment. Nonetheless, previous studies determined tissues with overexpression of ⍺-galactosidase A did not translate into pathological or negative outcomes in mice models. This suggests that an uncontrolled increase of the enzyme due to this therapy may not generate important adverse effects.

To this date, enzyme therapy remains the most accepted treatment for PD and uses hematopoietic stem and progenitor cells (HSPC); regardless, this method still has many limitations, hence the importance of proposing novel therapeutic alternatives.

“T-Rapa micropharmacies may be used to provide a continual source of enzymes compared to [enzyme therapy]. This may alleviate some issues with conventional enzyme therapy and address some difficulties of using HSPC-directed platforms alone,” the authors concluded.


Nagree M, Felizardo T, Faber M, et al. Autologous, lentivirus‐modified, T‐rapa cell “micropharmacies” for lysosomal storage disorders. EMBO Mol Med. 2022;e14297. doi:10.15252/emmm.202114297