08 | Combination therapy targeting HDAC8 and SIRT1 improves muscle integrity in a Duchenne muscular dystrophy zebrafish model

Sabrina Carbone¹, A. Brix¹, L. Lociuro¹, O. Gjana¹, L. Belleri², M. Schiavone³, A. Marozzi¹, F. Del Bene², C. De Palma¹, A. Pezzotta¹, A. Pistocchi¹ | ¹Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy; ²Sorbonne Université, INSERM U968, CNRS UMR 7210, Institut de la Vision, Paris, France; ³Department of Molecular and translational medicine, Università degli Studi di Brescia, Brescia, Italy.

Duchenne Muscular Dystrophy (DMD) is a severe genetic disease causing progressive muscle degeneration, inflammation, and fibrosis. While gene and cell therapies offer promising therapeutic avenues, their complexity makes pharmacological approaches more accessible. Histone deacetylases (HDACs) are a family of epigenetic regulators found deregulated in DMD patients. Indeed, the modulation of HDACs has emerged as a key strategy with Givinostat, a pan-HDAC inhibitor, recently being approved by the FDA. However, the use of pan inhibitors has been associated with many side effects. Indeed, the treatment with selective compounds might reduce the off-targets, while maintaining the therapeutic effects. Specifically, inhibiting HDAC8 with PCI-34051 restores the muscle function, acting on the stabilization of the cytoskeleton, while the activation of SIRT1 with SRT2104 improves the energy metabolism and muscle regeneration, acting on the mitochondrial biogenesis. In our study, we evaluated a novel combination therapy involving HDAC8 inhibition and SIRT1 activation. In dmd zebrafish embryos, the co-administration of PCI-34051 and SRT2104 restores the muscle loss and reduces the inflammation. Importantly, the combination therapy allowed for lower doses of each compound, maximizing therapeutic effects while minimizing potential side effects. These findings underline the potential of HDAC8 inhibition and SIRT1 activation as an interesting therapeutic strategy to be exploited for DMD patients, both in single and in combination settings.