HDAC inhibitors as pharmacological treatment for Duchenne muscular dystrophy: a discovery journey from bench to patients

Abstract

Earlier evidence that targeting the balance between histone acetyltransferases (HATs) and deacetylases (HDACs), through exposure to HDAC inhibitors (HDACis), could enhance skeletal myogenesis, prompted interest in using HDACis to promote muscle regeneration. Further identification of constitutive HDAC activation in dystrophin-deficient muscles, caused by dysregulated nitric oxide (NO) signaling, provided the rationale for HDACi-based therapeutic interventions for Duchenne muscular dystrophy (DMD). In this review, we describe the molecular, preclinical, and clinical evidence supporting the efficacy of HDACis in countering disease progression by targeting pathogenic networks of gene expression in multiple muscle-resident cell types of patients with DMD. Given that givinostat is paving the way for HDACi-based interventions in DMD, next-generation HDACis with optimized therapeutic profiles and efficacy could be also explored for synergistic combinations with other therapeutic strategies.

Keywords: HDAC inhibitors; duchenne muscular dystrophy; fibro-adipogenic degeneration; histone acetylation; muscle regeneration.

Figure 1:. Multiple levels HDACi effects on DMD-related pathogenic events

Schematic illustration of the multitude of cell types and functional interactions targeted by HDACi in DMD muscles. Pathogenic events triggered by dystrophin deficiency promote DMD progression and are therefore potential targets for interventions aimed at halting disease progression. Compelling evidence indicates that the mechanism responsible for the beneficial action of HDACi in DMD muscles is multifaceted and occurs through effects on multiple cell types and at various levels.

Figure 2:. HDACi-mediated regulation of FAP lineage plasticity in DMD muscles

A) Mechanistic model of HDACi-mediated reprogramming of FAPs towards the myogenic lineage. HDACi induce expression of myoMiRs, MyoD and BAf60c. MyoMiRs degrade the alternative Baf60 complex subunits (Baf60a/b); and MyoD/Baf60c cooperate to activate transcription of muscle-specific genes. B) Model of stable repression of myogenic lineage in FAPs. Chromatin regions containing muscle-specific genes (depicted in red) are sequestered to the peripheral heterochromatic compartment, in close proximity to the nuclear lamina (NL). Here, the transcription factor Prdm16 interacts with the H3K9 KMTs G9a/GLP which catalyze H3K9me2 on regulatory elements of myogenic genes, mediating their repression and confinement at the NL (upper panel). Inhibition of G9a/GLP complex induces relocalization of chromatin regions encoding myogenic genes (in red) away from the NL and a consequent de-repression (lower panel). C-D) Schematic representation of Waddington epigenetic landscapes at early (C) and late (D) stages of DMD progression to depict FAPs lineage plasticity in response to HDACi. In the highly regenerative environment of dystrophic muscles at early stages of DMD (C) HDACi are capable to overcome the epigenetic barrier imposed by H3K9 methylation, which prevent FAPs to undertake the myogenic path, thus inducing reprogramming towards the myogenic lineage. Conversely, we speculate that in degenerated DMD muscles at late stages of the disease (D), FAPs are resistant to myogenic reprogramming because of a higher epigenetic barrier likely represented by H3K9 methylation.

Figure I

Illustration of the full spectrum of events regulated by histone and non-histone acetylation at the nuclear and cytoplasmic level