22 | Subcutaneous injection of microencapsulated Sertoli cells is more efficacious than deflazacort treatment in mdx mice

Sara Chiappalupi^1|2, G. Gentili^1|2, L. Salvadori^2|3, I. Arato¹, F. Mancuso¹, M. Paiella^1|2, F. Riuzzi^1|2, R. Calafiore¹, G. Luca¹, G. Sorci^1|2 | ¹Department of Medicine and Surgery, University of Perugia, Italy; ²Interuniversity Institute of Myology (IIM), Perugia, Italy; ³Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy. | S. Chiappalupi and G. Sorci shared Senior authorship; S. Chiappalupi and G. Gentili contributed equally.

Duchenne muscular dystrophy (DMD) is an X-linked disease due to mutations in the dystrophin gene and characterized by progressive muscle degeneration and chronic inflammation, leading to premature death. Multiple therapeutic approaches are under evaluation, although showing limited efficacy, requiring pharmacological immunosuppression, and associated with several side effects. Testicular Sertoli cells (SeC) are endowed with peculiar immunomodulatory and trophic properties. Intraperitoneal (i.p.) injection of porcine SeC encapsulated into clinical-grade alginate microcapsules (MC-SeC) in mdx mice resulted in a dramatic reduction of muscle inflammation, fibrosis, and necrosis, and induction of utrophin expression, leading to recovery of muscle performance [1]. We demonstrated that, in 4-week-old male mdx mice, a single subcutaneous injection of MC-SeC is as beneficial as the intraperitoneal one, in both short- and long-term treatments, and results in long-term beneficial effects on the heart, reducing fibrosis, with no side effects observed in other organs. Diaphragm, which accumulates damage over time in the mdx model, showed a dramatic reduction of fibrous and adipose tissue accumulation 5 months after s.c. injection with MC-SeC, which appeared more efficacious than treatment with Deflazacort alone. However, the use of MC-SeC in combination with Deflazacort translated into reduced efficacy compared to the single treatments in terms of skeletal muscle morphology and functionality, likely due to interference between the signaling pathways activated by the two anti-inflammatory approaches. Our data suggest that a single s.c. injection of MC-SeC represents a safe and universal approach, endowed with several advantages over the current therapeutic interventions, to treat DMD and BMD patients.