Enhancement of Prednisolone efficacy and safety in Duchenne muscular dystrophy via neutrophil elastase inhibition

Johnson, K. A.; Jones, F. K.; Ghadiali, R. S.; Luke, T.-H. A.; Sweeney, M. D.; Moffitt, R. A.; Mamchaoui, K.; Ricci, E.; Young, I.; Pisconti, A.

doi:10.1101/2025.02.26.640472

bioRxiv · 10.1101/2025.02.26.640472

Enhancement of Prednisolone efficacy and safety in Duchenne muscular dystrophy via neutrophil elastase inhibition

Johnson, K. A.·Jones, F. K.·Ghadiali, R. S.·Luke, T.-H. A.·Sweeney, M. D.·Moffitt, R. A.·Mamchaoui, K.·Ricci, E.·Young, I.·Pisconti, A.

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Abstract

Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by muscle wasting, and leading to premature death. The pathogenesis of DMD is complex. It is triggered by loss of the cytoskeletal protein dystrophin, which causes muscle fiber instability and damage, followed by chronic inflammation and fibrotic replacement of damaged muscle tissue. Here we investigated the hypothesis that inhibition of neutrophil elastase, which is increased in dystrophic mice and impairs myogenesis, could provide a therapeutic effect in DMD. While neutrophil elastase inhibition, via the orally bioavailable compound Alvelestat, enhances myogenesis both in vitro and in vivo and reduces muscle damage and fibrosis, it does not produce a significant beneficial effect on the functional outcomes. However, when co- administered with the standard of care Prednisolone, Alvelestat dramatically enhances Prednisolone efficacy in a mouse model of DMD. In key functional tests, the performance of mice co-dosed with Alvelestat and Prednisolone is almost three times better than that of mice treated with Prednisolone alone. Additionally, co-administration of Alvelestat and Prednisolone reduces Prednisolones negative effects on muscle mass and resistance to fatigue. These findings are consistent with the finding that Prednisolone induces neutrophil elastase expression in patients affected by DMD. Our data support a beneficial role for neutrophil elastase inhibition in a mouse model of DMD that is also treated with Prednisolone, suggesting that a combinatorial therapy for DMD including a corticosteroid and a neutrophil elastase inhibitor could be trialed in humans. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/640472v3_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@f20853org.highwire.dtl.DTLVardef@b7fforg.highwire.dtl.DTLVardef@12fe312org.highwire.dtl.DTLVardef@e4cf0c_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Johnson, K. A., Jones, F. K., Ghadiali, R. S., Luke, T.-H. A., Sweeney, M. D., Moffitt, R. A., Mamchaoui, K., Ricci, E., Young, I., Pisconti, A.. 2025-02-27. Enhancement of Prednisolone efficacy and safety in Duchenne muscular dystrophy via neutrophil elastase inhibition. https://doi.org/10.1101/2025.02.26.640472

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