Objective: Mitochondrial dysfunction in Friedreich’s Ataxia (FRDA) results from GAA repeat expansion in the FXN gene, reducing frataxin levels thus disrupting iron-sulfur clusters essential for mitochondrial electron transport and iron homeostasis. We tested a synthetic nano-enzyme Pleozyme for its protective effects in human FRDA-iPSC-derived cells with and without FRDA approved SKYCLARYS® (Omaveloxolone). Pleozymes catalyze superoxide dismutation, facilitate mitochondrial electron transfer and oxidize hydrogen sulfide into polysulfides, a mechanism to increase the antioxidant transcription factor Nrf2 release from Keap1. Pleozymes co-localize to mitochondria and improve outcome in acute brain injury models.

Background: FRDA associated cardiomyopathy, a leading cause of premature mortality, is characterized by left ventricular hypertrophy and fibrosis leading to heart failure. Frataxin deficiency triggers mitochondrial proliferation.  Omaveloxolone targets the Nrf2 antioxidant pathway, however disease progression still occurs. Frataxin deficiency and gene therapy, while advancing remain challenging. Pleozymes, a biocompatible synthetic nano-enzyme, offers a potential alternative enhancing mitochondrial and non-mitochondrial bioenergetics while reducing superoxide radical.

Method: Pleozyme was synthesized from activated charcoal are oxidized, PEGylated forming 5–7 nm graphene-based discs with broad redox activity yielding a broad redox potential spanning crucial electron transfer reactions without off target metabolic effects.. A deferoxamine-conjugated variant (DEF-PEG-OAC) was engineered for iron chelation. We tested FRDA patient-derived iPSCs and isogenic controls differentiated into cardiomyocytes, assessing metabolic function via Seahorse analysis, lipid peroxidation via Click-iT assay, Nrf2 activation via immunofluorescence, and contractility via IonOptix CytoMotion Lite System.

Results: FRDA cardiomyocytes exhibited a 74.5% reduction in maximal respiration and a 53% decline in contractility compared to controls (p < 0.000001). Treatment with DEF-PEG-OAC improved maximal respiration by 16% and fully restored contractility (p < 0.0001). Pleozyme increased nuclear Nrf2 localization by 52%, an effect additive with omaveloxolone (p < 0.05), likely through Keap1 persulfidation.

Conclusion: These findings demonstrate Pleozyme’s ability to improve mitochondrial bioenergetics, reduce oxidative stress, and restore cardiomyocyte function in FRDA models. The study provides strong preclinical evidence supporting further in vivo evaluation and potential clinical translation of Pleozyme as a novel therapy for FRDA and related mitochondrial dysfunction.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pleozymes-a-multifunctional-nanozyme-for-targeting-metabolic-deficits-in-friedreichs-ataxia/