Epigenetic therapy for Friedreich ataxia

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Friedreich ataxia (FRDA) is a fatal, inherited neurodegenerative disorder.
• Current treatments for FRDA are limited, necessitating novel therapeutic approaches.
• Epigenetic dysregulation, specifically histone modification, is implicated in FRDA pathogenesis.

Purpose of the Study:

• To evaluate the efficacy of a novel histone deacetylase inhibitor (HDACi), RG2833, in an in vitro model of FRDA.
• To assess the safety and efficacy of RG2833 in a Phase I clinical trial for FRDA patients.
• To investigate RG2833's impact on FXN gene expression and epigenetic modifications.

Main Methods:

• Developed a human FRDA neuronal cell model from induced pluripotent stem cells.
• Administered RG2833 to FRDA patients in a dose-escalation Phase I clinical trial (30-240 mg/day).
• Monitored adverse effects, FXN mRNA, frataxin protein, and histone modifications in patient blood cells.

Main Results:

• RG2833 increased FXN mRNA and frataxin protein levels in the FRDA neuronal cell model.
• Epigenetic analysis revealed histone H3 lysine 9 acetylation mediated by RG2833.
• FRDA patients showed increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood cells with no safety issues.

Conclusions:

• RG2833 effectively modulates epigenetic marks and gene expression in both in vitro and in vivo FRDA models.
• Therapeutic exposure levels in patients correlate with observed epigenetic changes.
• These findings support RG2833 as a potential epigenetic therapy for Friedreich ataxia.