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.