Nerve Ultrasound in Friedreich’s Ataxia: enlarged nerves as a Biomarker of disease severity

G. Di Pietro, E. Cioffi, P. Falco, E. Galosi, G. De Stefano, G. Di Stefano, C. Leone, V. Martines, S. Perotti, C. Casali, A. Truini, Nerve Ultrasound in Friedreich’s Ataxia: enlarged nerves as a Biomarker of disease severity, Clinical Neurophysiology, 2024, ISSN 1388-2457, doi:10.1016/j.clinph.2024.01.004 

 Our study now shows that high-resolution nerve ultrasound examination can detect nerve enlargements in patients with Friedreich's ataxia (mostly at the level of upper limbs). Neve ultrasound abnormalities correlate with clinically established variables in patients with Friedreich's ataxia. This technique, therefore, might be a promising biomarker for measuring disease severity and treatment effects in this rare and severely disabling condition.

Protective effect of FXN overexpression on ferroptosis in L-Glu-induced SH-SY5Y cells

Mengran Wang, Tingting Xuan, Haining Li, Jing An, Tianhui Hao, Jiang Cheng, Protective effect of FXN overexpression on ferroptosis in L-Glu-induced SH-SY5Y cells, Acta Histochemica, Volume 126, Issue 1, 2024, 152135, ISSN 0065-1281, doi:10.1016/j.acthis.2024.152135. 

 To conclude, our research demonstrates that an elevated expression of FXN effectively demonstrates a robust neuroprotective effect against oxidative damage induced by L-Glu. Moreover, it mitigates mitochondrial dysfunction and lipid metabolic dysregulation associated with ferroptosis. FXN overexpression holds promise in potential therapeutic strategies for AD by inhibiting ferroptosis in nerve cells and fostering their protection.

Anti-gene oligonucleotides targeting Friedreichs ataxia expanded GAA:TTC repeats increase Frataxin expression

Anti-gene oligonucleotides targeting Friedreichs ataxia expanded GAA:TTC repeats increase Frataxin expression, Negin Mozafari, Salome Isabel Marques Milagres, Cristina Simoes Jesus Rocha, Claudia Marina Vargiu, Fiona Freyberger, Osama Saher, Tea Umek, Pontus Blomberg, Per Trolle Jorgensen, Edvard Carl Igne Smith, Jesper Wengel, Rula L Zain, bioRxiv 2024.01.25.577034; doi:10.1101/2024.01.25.577034 

We examined numerous LNA-DNA AGOs and found that the design, length and their LNA composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed ONs targeting the GAA:TTC DNA repeats to upregulate FXN gene expression.

Omaveloxolone for the treatment of Friedreich Ataxia: clinical trial results and practical considerations

David R Lynch, Susan Perlman & Kim Schadt (2024) Omaveloxolone for the treatment of Friedreich Ataxia: clinical trial results and practical considerations, Expert Review of Neurotherapeutics, DOI: 10.1080/14737175.2024.2310617 

Omaveloxolone provides a significant advance in treatment of FRDA that is likely to be beneficial in a majority of the FRDA population. The data suggesting a benefit is consistent, and adverse issues are relatively modest. The major remaining questions are the subgroups that are most responsive and how long the beneficial effects will remain significant in FRDA patients.

Emerging antioxidant therapies in Friedreich's ataxia

Fred J. Edzeamey, Zenouska Ramchunder, Charareh Pourzand, Sara Anjomani Virmoun, Front. Pharmacol. Sec. Experimental Pharmacology and Drug Discovery, Volume 15 - 2024 | doi: 10.3389/fphar.2024.1359618 

The confirmation of oxidative stress as one of the pathological signatures of FRDA led to the search for antioxidants which can be used as therapeutic modality. Based on this observation, antioxidants with different mechanisms of action have been explored for FRDA therapy since the last two decades. In this review, we bring forth all antioxidants which have been investigated for FRDA therapy and have been signed off for clinical trials. We summarise their various target points in FRDA disease pathway, their performances during clinical trials and possible factors which might have accounted for their failure or otherwise during clinical trials. We also discuss the limitation of the studies completed and propose possible strategies for combinatorial therapy of antioxidants to generate synergistic effect in FRDA patients. treatment modality for FRDA.

Omaveloxolone: a groundbreaking milestone as the first FDA-approved drug for Friedreich ataxia

Pilotto, Federica et al., Trends in Molecular Medicine, Volume 0, Issue 0. doi:10.1016/j.molmed.2023.12.002 

 Omaveloxolone represents the first FDA-approved drug for Friedreich’s ataxia (FA). Omaveloxolone targets nuclear factor erythroid 2-related factor 2 (NRF2), which is a master regulator in the antioxidant pathway. The omaveloxolone clinical trial serves as an example for future design of clinical trials. A resolutive cure for FA would probably be achieved only via combinatorial therapy.

AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of friedreich’s ataxia

Chang, J. C., Ryan, M. R., Stark, M. C., Liu, S., Purushothaman, P., Bolan, F., Johnson, C. A., Champe, M., Meng, H., Lawlor, M. W., Halawani, S., Ngaba, L. V., Lynch, D. R., Davis, C., Gonzalo-Gil, E., Lutz, C., Urbinati, F., Medicherla, B., & Fonck, C. (2024). AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of friedreich’s ataxia. Molecular Therapy. Methods & Clinical Development, 101193, 101193. doi:10.1016/j.omtm.2024.101193

 Frataxin protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild-type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.

METTL17 is an Fe-S cluster checkpoint for mitochondrial translation

METTL17 is an Fe-S cluster checkpoint for mitochondrial translation. Tslil Ast,Yuzuru Itoh,Shayan Sadre,Jason G. McCoy,Gil Namkoong,Jordan C. Wengrod,Ivan Chicherin,Pallavi R. Joshi,Piotr Kamenski,Daniel L.M. Suess,Alexey Amunts,Vamsi K. Mootha. Molecular Cell 84, 359–374, January 18, 2024. Doi:10.1016/j.molcel.2023.12.016 

METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN-depleted cells. These findings suggest that METTL17 acts as an Fe-S cluster checkpoint, promoting translation of Fe-S cluster-rich oxidative phosphorylation (OXPHOS) proteins only when Fe-S cofactors are replete.

Gene editing improves Endoplasmic reticulum-mitochondrial contacts and Unfolded Protein Response in Friedreich's Ataxia iPSC-derived neurons

Priyanka Mishra, Anusha Sivakumar, Avalon Johnson, Carla Pernaci, Anna S. Warden, Lilas Rony El- Hachem, Emily Hansen1, Rafael A. Badell-Grau, VEENITA KHARE, Gabriela Ramirez, Sydney Gillette, Peng Guo, Nicole Coufal, Stephanie Cherqui. Front. Pharmacol., Sec. Neuropharmacology, Volume 15 - 2024 | doi: 10.3389/fphar.2024.1323491

Taken together, these results represent a novel finding for disease pathogenesis showing dramatic ER structural damage in FRDA, validate the efficacy profile of our FXN gene editing approach in a disease relevant model, and support our approach as an effective strategy for therapeutic intervention for Friedreich's ataxia.

Iron imbalance in neurodegeneration

Levi, S., Ripamonti, M., Moro, A.S. et al. Iron imbalance in neurodegeneration. Mol Psychiatry (2024). doi:10.1038/s41380-023-02399-z 

 This protein plays a key role in delivering iron to the ISC complex machinery. A second example is a rare disease known as sideroblastic anemia with X-linked ataxia (XLSA/A), which is caused by defects in ABCB7, the mitochondrial transporter of the cytosolic ISC precursor [141], which is essential for the maturation of cytosolic ISC proteins. This condition reflects the importance of the mitochondrion in the synthesis of ISC and in maintaining cellular homeostasis.