Safety and efficacy of omaveloxolone v/s placebo for the treatment of Friedreich's ataxia in patients aged more than 16 years: a systematic review

Umrao, A., Pahuja, M. & Chatterjee, N.S. Safety and efficacy of omaveloxolone v/s placebo for the treatment of Friedreich's ataxia in patients aged more than 16 years: a systematic review. Orphanet J Rare Dis 19, 495 (2024). doi:10.1186/s13023-024-03474-6 

The results of the Omav treatment indicated a persistent benefit to FA patients who received Omav for an extended period. The greater effect on longer GAA lengths than shorter repeats and the lower degree of improvement in pes cavus patients suggest that Omav aims for the most severe or progressive abnormalities in FA patients in a time-dependent manner.

Therefore, based on the available literature and the quality of the studies, further randomized controlled trials may include patients with progressive disease with the consideration of pes cavus, foot deformity. Considering the progressive nature of the disease, long-term follow-up beyond three years to constantly evaluate the effect of Omav on FA patients shall be considered.

Health-Related Quality of Life in Patients with Friedreich Ataxia Using Mobility Assistive Technologies: Limited Fit of the EQ-5D-3L Mobility Dimension

Health-Related Quality of Life in Patients with Friedreich Ataxia Using Mobility Assistive Technologies: Limited Fit of the EQ-5D-3L Mobility Dimension. Maresa Buchholz, Michelle Pfaff, Audrey Iskandar, Kathrin Reetz, Jörg B. Schulz, Marcus Grobe-Einsler, Thomas Klockgether, Bernhard Michalowsky, EFACTS Study Group, Neurology and Therapy, Print ISSN: 2193-8253, Elektronische ISSN: 2193-6536, DOI: 10.1007/s40120-024-00694-7 

There are concerns about using HRQoL measures, such as the EQ-5D, in mobility-impaired individuals who had difficulties finding appropriate response options for mobility-related items. Our findings demonstrated limitations of the EQ-5D-3L mobility item in patients with FA using MAT, detecting a noticeable amount of non-responses in the mobility item in wheelchair users and a tendency to the mid-response level “some problems” in individuals using walking aids.

Repairing muscle with broccoli-derived sulforaphane: A preclinical evaluation for the treatment of mitochondrial myopathies

Thomas Lilley, Donny M. Camera, Faith A.A. Kwa, Repairing muscle with broccoli-derived sulforaphane: A preclinical evaluation for the treatment of mitochondrial myopathies, Drug Discovery Today, n2024, 104283, ISSN 1359-6446, doi:10.1016/j.drudis.2024.104283. 

Nrf2 upregulates mitochondrial gene expression pathways associated with improved mitochondrial substrate metabolism [peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) and frataxin (FXN)], mitochondrial biogenesis, and mitochondrial adenosine triphosphate (ATP) production via oxidative phosphorylation (OXPHOS).

Sulforaphane-induced Nrf2 expression has been linked to several reparative pathways key to the pathogenesis of mitochondrial dysfunction and pertinent to mitochondrial myopathies such as sarcopenia, proximal myopathy, CPEO, and Friedreich ataxia, including antioxidant system upregulation, inflammatory downregulation, upregulated expression of mitochondrial-related genes such as FXN, and increased muscle mass and function.

Plasma miRNAs Correlate with Structural Brain and Cardiac Damage in Friedreich’s Ataxia

Peluzzo, T.M., Vieira, A.S., Matos, A.H.B. et al. Plasma miRNAs Correlate with Structural Brain and Cardiac Damage in Friedreich’s Ataxia. Cerebellum 24, 15 (2025). https://doi.org/10.1007/s12311-024-01766-y 

Our results showed that miR-26a-5p is upregulated and miR-15a-5p is downregulated. The first was correlated with age at onset, cerebellum volume, spinal cord cross-sectional area (C2-CSA) and the left ventricle mass (LV_Mass). For the miR-15a-5p, significant correlations were found with cerebellum volume, spinal cord eccentricity and LV_Mass. It has been previously hypothesized that these miRs target BDNF, modulating its expression and, when this gene is downregulated, it leads to neuronal loss, explaining the ataxic phenotype and our results reinforce this hypothesis. The miR-26a-5p was already associated with cardiomyocyte hypertrophy through the increased NLRP3 inflammasome activity, which is indirectly linked with cardiac hypertrophy. Considering that, we propose these miRNAs as possible prognostic biomarkers for FRDA. However, longitudinal studies are still needed to validate their clinical use.

Management of Friedreich Ataxia–Associated Cardiomyopathy in Pregnancy: A Review of the Literature

Management of Friedreich Ataxia–Associated Cardiomyopathy in Pregnancy: A Review of the Literature, Peterson, Ashleigh N. et al., American Journal of Cardiology, Volume 210, 118 - 129, DOI: 10.1016/j.amjcard.2023.10.019 

A major manifestation of Friedreich ataxia (FRDA) is cardiomyopathy, caused by mitochondrial proliferation in myocytes. Because the lifespan for patients with FRDA improves with better treatment modalities, more patients are becoming pregnant, meaning that more medical providers must know how to care for this population. This report provides a review of the literature on multidisciplinary management of pregnant patients with FRDA and cardiomyopathy from preconception through lactation.

Low expression of Frataxin might contribute to diabetic peripheral neuropathy in a mouse model

Siyu Xia, Lin Wu, Jing Chen, Kuanyu Li, Dezhi Bian, Low expression of Frataxin might contribute to diabetic peripheral neuropathy in a mouse model, Biochemical and Biophysical Research Communications, Volume 744, 2025, 151228, ISSN 0006-291X, doi:10.1016/j.bbrc.2024.151228.  

Diabetes is one of the most prevalent metabolic disorders, and its incidence has been experiencing a steady annual rise in recent years. Diabetic peripheral neuropathy (DPN) represents the most frequent adverse complication, exerting a profound impact on the quality of life for those suffering from diabetes. The etiology of DPN is complex, including impaired mitochondrial function. Iron-sulfur clusters (Fe–S) are essential cofactors for numerous essential enzymes crucial for mitochondrial function. Our previous study showed that expression of Frataxin, encoded by the Fxn gene, is downregulated in leptin receptor knockout (so-called db/db) mice, a commonly used DPN mouse model. Fxn is one of the core components of Fe–S biogenesis machinery. Here, we found that the mitochondria-targeted antioxidant SS-31 markedly improved the behavioral indices and significantly mitigated the damage to the sciatic nerve. SS-31 treatment effectively elevated Fxn expression, meliorated mitochondrial function, and inflammation in the sciatic nerve (SCN). We also found that SS-31 effectively mitigated high glucose-induced disruption of iron and redox homeostasis in RSC96 cells, a typical cell model of DPN, thereby improving mitochondrial function. These findings suggest enhancing Fe–S biogenesis could be an effective therapeutic strategy for treating DPN.

Characterization of Arabidopsis thaliana FRATAXIN HOMOLOG in heme catabolism

Jing Zhang, Yingying Zhou, Qianyi Duan, Xinhe Xu, Xiao Wang, Jia Wang, Lin Liu, Characterization of Arabidopsis thaliana FRATAXIN HOMOLOG in heme catabolism, Biochimie, 2024, doi:10.1016/j.biochi.2024.12.010. 

Frataxin plays vital roles in various iron related processes. Arabidopsis thaliana FRATAXIN HOMOLOG (AtFH) is the first identified plant frataxin and has been found to regulate the last step of heme biosynthesis. Here, we report of the involvement of AtFH in heme catabolism by regulating the activity of heme oxygenase. AtFH forms a homodimer, and its crystal structure shows the dimeric interactions. A structural comparison with known frataxin structures suggests the iron binding sites, and the site for heme oxygenase activity is possibly located in a region containing Glu78. The results indicate a previously uncharacterized role of plant frataxin in heme catabolism.

Tachycardiomyopathy Treated With Ablation by Using 3D Mapping System in a Patient With Friedreich Ataxia

Hayıroğlu Mİ, Kalenderoğlu K, Gürkan K. Tachycardiomyopathy Treated With Ablation by Using 3D Mapping System in a Patient With Friedreich Ataxia. Pacing Clin Electrophysiol. 2024 Dec 24. doi: 10.1111/pace.15125. Epub ahead of print. PMID: 39717928. 

This report highlights the importance of a multidisciplinary approach in diagnosing and treating cardiac manifestations in patients with Friedreich ataxia, as well as the efficacy of 3D mapping technology in guiding successful ablation therapies.

Frataxin deficiency in the astrocytes drives neurocognitive impairment in sickle cell disease mice

Frataxin deficiency in the astrocytes drives neurocognitive impairment in sickle cell disease mice Enrico M Novelli, Shane Lenhart, Lesley M Foley, Nandinii Sekar, Paritosh Mondal, Hong Wang, T Kevin Hitchens, Samit Ghosh, Stephen Y Chan, Xiaoming Hu, Rimi Hazra, bioRxiv 2024.12.20.629760; doi:10.1101/2024.12.20.629760

Pharmacological induction of FXN by administration of insulin growth factor-1 improved cognitive function in the SSFXN-KO mice. Overall, our data demonstrate that FXN is a critical factor regulating neuroaxonal health and cognitive function in SCD mice. FXN may therefore be a novel pharmacologic target to prevent cerebrovascular complications in SCD.

PTC Therapeutics Announces Vatiquinone NDA Submission to FDA for the Treatment of Children and Adults Living with Friedreich Ataxia

WARREN, N.J., Dec. 19, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) announced today the submission of the vatiquinone New Drug Application (NDA) for the treatment of children and adults living with Friedreich ataxia (FA) to the U.S. Food and Drug Administration (FDA). 

The application is supported by data from a placebo-controlled study and two long-term studies that included pediatric and adult patients. 

Results from the three studies indicated significant, durable, and clinically meaningful evidence of slowing disease progression with vatiquinone.

Vatiquinone is known as a first-in-class selective inhibitor of 15-Lipoxygenase (15-LO), "an enzyme that is a key regulator of the energetic and oxidative stress pathways that are disrupted in Friedreich ataxia," according to PTC.

Larimar Therapeutics Announces Positive Initial Data from Ongoing Long-term Open Label Extension Study & Progress Across Nomlabofusp Program for Friedreich’s Ataxia

December 16, 2024. Source: Larimar Therapeutics BALA CYNWYD, Pa., Dec. 16, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), today announced positive initial data from the ongoing long-term OLE study evaluating daily subcutaneous injections of 25 mg of nomlabofusp self-administered or administered by a caregiver in participants with FA. 

The Company also provided a nomlabofusp development program update. 

We are pleased with the advancement of our OLE study that includes 14 patients dosed for up to 260 days. Importantly, 25 mg of nomlabofusp administered daily increased and maintained tissue FXN levels over time, with mean levels increasing from 15% of healthy volunteers at baseline to 30% in buccal cells and from 16% to 72% in skin cells at Day 90. At the time of data cut off for the OLE study, 14 adults with FA were included with up to 260 days (mean 99 days) of long-term daily treatment of 25 mg of nomlabofusp. Among these patients, more than 50% were non-ambulatory.

Larimar Therapeutics Reports Positive Initial Data from Nomlabofusp OLE Study for Friedreich’s Ataxia

Dec. 16, 2024. Larimar Therapeutics announced positive results from its ongoing open label extension study evaluating the daily subcutaneous administration of 25 mg nomlabofusp in participants with Friedreich’s ataxia. In a cohort of 14 patients, the treatment was generally well tolerated for up to 260 days, with tissue frataxin levels significantly increasing in both buccal and skin cells by Day 90. 

Plans for a global confirmatory study are set for mid-2025, with a Biologics License Application targeted for submission in the second half of 2025. Early trends towards improvement in clinical outcomes observed at Day 90, supporting the potential for nomlabofusp to benefit a broad spectrum of patients with Friedreich’s ataxia.

Serious adverse events occurred in two study participants during the OLE study, which, despite resolving quickly, may raise concerns about the safety profile of nomlabofusp.

Gradient of microstructural damage along the dentato- thalamo-cortical tract in Friedreich ataxia

Sirio Cocozza, Sara Bosticardo, Matteo Battocchio, Louise Corben, Martin Delatycki, Gary Egan, Nellie Georgiou-Karistianis, Serena Monti, Giuseppe Palma, Chiara Pane, Francesco Sacca, Simona Schiavi, Louisa Selvadurai, Mario Tranfa , Alessandro Daducci, Arturo Brunetti & Ian H. Harding. Gradient of microstructural damage along the dentato- thalamo-cortical tract in Friedreich ataxia. Annals of Clinical and Translational Neurology 2024; 11(7): 1691–1702. doi: 10.1002/acn3.52048

Our study further expands the current knowl- edge about brain involvement in FRDA, showing that microstructural abnormalities within the DTT are weighted to early segments of the tract (i.e., the superior cerebellar peduncle). These findings are consistent with the hypothesis of DTT undergoing anterograde degeneration arising from the dentate nuclei and progressing to the primary motor cortex.

Ignition of Small Molecule Inhibitors in Friedreich's Ataxia with Explainable Artificial Intelligence

Kübra Kirboğa, K., Küçüksille, E., & Kose, U. (2023). Ignition of Small Molecule Inhibitors in Friedreich's Ataxia with Explainable Artificial Intelligence. BRAIN. Broad Research In Artificial Intelligence And Neuroscience, 14(3), 287-313. Retrieved from https://brain.edusoft.ro/index.php/brain/article/view/1427

The results showed the importance of properties related to nitrogen-containing functional groups (SHAP value of PubchemFP656 is -0.29) and aromatic rings (SHAP value of PubchemFP12 is -0.16). As a result, we explained the effect of the molecular fingerprints on the models and the impact on possible drugs that can be developed for FA with artificial intelligence (XAI), which can be explained through SHAP (Shapley Additive Explanations) values. Model scripts and fingerprinting methods are also available at https://github.com/tissueandcells/XAI.

Altered calcium responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes

Marullo, Chiara & Croci, Laura & Giupponi, Iris & Rivoletti, Claudia & Zuffetti, Sofia & Bettegazzi, Barbara & Cremona, Ottavio & Giunti, Paola & Ambrosi, Alessandro & Casoni, Filippo & Consalez, Gian & Codazzi, Franca. (2024). Altered calcium responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes. Journal of cell science. 10.1242/jcs.263446.

Our findings shed light on cellular changes caused by FXN downregulation in cerebellar astrocytes, likely impairing their complex interaction with neurons. The potentially impaired ability to provide neuronal cells with glutathione or to release neuromodulators in a calcium-dependent manner could affect neuronal function, contributing to neurodegeneration.

Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy

Salinas L, Montgomery CB, Figueroa F, Thai PN, Chiamvimonvat N, Cortopassi G, Dedkova EN. Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy. Commun Biol. 2024 Oct 3;7(1):1250. doi: 10.1038/s42003-024-06962-4. PMID: 39363102; PMCID: PMC11449905. 

 The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKIIδ) was decreased significantly more in Fxn-cKO males. This is the first study that extensively investigates the sexual dimorphism in FA mouse model with cardiac calcium signaling impairment.

Lack of Concentration-QTc Relationship and Cardiac Risk With Vatiquinone Therapeutic and Supratherapeutic Doses

Lee L, Flach S, Xue H, Arivelu L, Golden L, Kong R, Darpo B. Lack of Concentration-QTc Relationship and Cardiac Risk With Vatiquinone Therapeutic and Supratherapeutic Doses. Clin Pharmacol Drug Dev. 2024 Nov;13(11):1227-1238. doi: 10.1002/cpdd.1476. Epub 2024 Oct 17. PMID: 39415654. 

 No new safety signals were found, as safety data are consistent with the known safety profile of vatiquinone. These findings altogether demonstrated that there is a minimal cardiac risk for vatiquinone concentrations up to the supratherapeutic dose level.

Friedreich Ataxia

Bidichandani SI, Delatycki MB, Napierala M, Duquette A. Friedreich Ataxia. 1998 Dec 18 [updated 2024 Oct 31]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301458. 

 Review (Last Update: October 31, 2024.)

Efficacy of Stabilometric Platform to Improve Standing Balance in Patients with Friedreich's Ataxia

ClinicalTrials.gov ID NCT06692296. Sponsor IRCCS Eugenio Medea. Last Update Posted 2024-11-21

The primary objective is to evaluate the potential effectiveness of an individualized intensive rehabilitation intervention using the "Prokin 252" stabilometric platform in the treatment of adolescent and adult patients with Friedreich's Ataxia. The secondary objective is to assess the retention of the rehabilitation treatment effects over time.

Omaveloxolone for the Treatment of Friedreich Ataxia: Efficacy, Safety, and Future Perspectives

Naghipour S, Corben LA, Hulme AJ, Dottori M, Delatycki MB, Lees JG, Lim SY. Omaveloxolone for the Treatment of Friedreich Ataxia: Efficacy, Safety, and Future Perspectives. Mov Disord. 2024 Nov 19. doi: 10.1002/mds.30070. Epub ahead of print. PMID: 39559924. 

The scarcity literature addressing the cardiovascular effects omaveloxolone in FRDA is concerning, especially considering that cardiomyopathy is the primary cause of mortality in affected individuals. Furthermore, the reported potential of omaveloxolone to induce mil elevations in B-natriuretic peptide (BNP), a known marker of heart failure, adds to this concern. Thus, those individuals with FRDA who have cardiomyopathy are advised to monitor BNP levels while using omaveloxolone. In this viewpoint, we examine the current literature on the efficacy and safety of omaveloxolone in treating FRDA, with a focus on its potential impact on cardiovascular health.

Assessment of the Clinical Interactions of GAA Repeat Expansions in FGF14 and FXN

Gerhart BJ, Pellerin D, Danzi MC, Zuchner S, Brais B, Matos-Rodrigues G, Nussenzweig A, Usdin K, Park CC, Napierala JS, Lynch DR, Napierala M. Assessment of the Clinical Interactions of GAA Repeat Expansions in FGF14 and FXN. Neurol Genet. 2024 Nov 20;10(6):e200210. doi: 10.1212/NXG.0000000000200210. PMID: 39574782; PMCID: PMC11581763.

Despite both molecular and clinical similarities between FRDA and SCA27B, the length of the GAA repeats in the FGF14 gene, including potentially pathogenic alleles, did not influence the clinical presentation of FRDA.

Recurrent DNA nicks drive massive expansions of (GAA)n repeats

Li L, Scott WS, Khristich AN, Armenia JF, Mirkin SM. Recurrent DNA nicks drive massive expansions of (GAA)n repeats. Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2413298121. doi: 10.1073/pnas.2413298121. Epub 2024 Nov 25. PMID: 39585990.

 We found that DNA nicks 5' of the (GAA)100 run led to a dramatic increase in both the rate and scale of its expansion in dividing cells. Strikingly, they also promoted large-scale expansions of carrier- and large normal-size (GAA)n repeats, recreating, in a model system, the expansion events that occur in human pedigrees. DNA nicks 3' of the (GAA)100 repeat led to a smaller but significant increase in the expansion rate as well. Our genetic analysis implies that in dividing cells, conversion of nicks into double-strand breaks (DSBs) during DNA replication followed by DSB or fork repair leads to repeat expansions. Finally, we showed that 5' GAA-strand nicks increase expansion frequency in nondividing yeast cells, albeit to a lesser extent than in dividing cells.

Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex

Steinhilper R, Boß L, Freibert SA, Schulz V, Krapoth N, Kaltwasser S, Lill R, Murphy BJ. Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex. Nat Commun. 2024 Dec 4;15(1):10559. doi: 10.1038/s41467-024-54585-4. PMID: 39632806; PMCID: PMC11618653.  

The structural interaction of FDX2 with the complex remains unclear. Here, we present cryo-EM structures of the human FDX2-bound core ISC complex showing that FDX2 and FXN compete for overlapping binding sites. FDX2 binds in either a 'distal' conformation, where its helix F interacts electrostatically with an arginine patch of NFS1, or a 'proximal' conformation, where this interaction tightens and the FDX2-specific C terminus binds to NFS1, facilitating the movement of the [2Fe-2S] cluster of FDX2 closer to the ISCU2 FeS cluster assembly site for rapid electron transfer. Structure-based mutational studies verify the contact areas of FDX2 within the core ISC complex.

Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability

Masnovo, C., Paleiov, Z., Dovrat, D. et al. Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability. Nat Commun 15, 10532 (2024). doi:10.1038/s41467-024-54977-6  

Here, we show that deficiency of the essential replisome component Mcm10 dramatically elevates (GAA)n repeat instability in a budding yeast model by loss of proper CMG helicase interaction. When repair is inefficient, such as in the case of RPA depletion, breakage of under-replicated repetitive DNA can occur during G2/M, leading to loss of essential genes and cell death. We hypothesize that the CMG-Mcm10 interaction promotes replication through hard-to-replicate regions, assuring genome stability and cell survival.

Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α

Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α. Hong Wang, … , Fumito Ichinose, Vamsi K. Mootha. Published December 2, 2024. J Clin Invest. 2024;134(23):e185569. doi:10.1172/JCI185569. 

Our results provide preclinical proof of concept that simultaneously enhancing Hb oxygen affinity while antagonizing HIF-2α can mimic the effects of continuous hypoxic breathing for therapeutic benefit. The regimen did not confer as impressive a lifespan rescue as continuous breathing of 11% oxygen, probably because GBT440 has a short half-life (6), and for practical reasons, we treated the mice five weekdays per week. Future studies in humans are required to evaluate the safety of this combination, given that hypoxia can be associated with acute and long-term side effects. Such safety studies could pave the path for first-in-human “hypoxia-in-a-pill” trials in patients with mitochondrial disease.