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.

Evaluating the therapeutic efficacy of SKYCLARYS: a promising FDA-approved drug for Friedreich ataxia treatment

 Ahmed, Usaid MBBSa; Afaq, Laiba MBBSa; Muhammad, Aqeel MBBSa; Riaz, Rumaisa MBBSa; Akilimali, Aymar MDb. Evaluating the therapeutic efficacy of SKYCLARYS: a promising FDA-approved drug for Friedreich ataxia treatment. International Journal of Surgery: Global Health 7(1):e0394, January 2024. | DOI: 10.1097/GH9.0000000000000394 

 Omaveloxone’s activation of the Nrf2 pathway, responsible for combating oxidative stress, has shown significant promise, especially in enhancing neurological function. Continuous research and the accumulation of clinical knowledge will play a crucial role in fine-tuning its best practices and investigating potential synergies with other treatments, all with the goal of further advancing the outcomes for those living with FRDA.

Tissue Iron in Friedreich Ataxia

Arnulf H Koeppen. Tissue Iron in Friedreich Ataxia. J. Integr. Neurosci. 2024, 23(1), 4. Doi:10.31083/j.jin2301004 (registering DOI) 

 Iron dysmetabolism in DRG is complex and consists of prominent expression of ferritin in hyperplastic satellite cells and residual nodules, also a loss of the iron export protein ferroportin from the cytoplasm of the remaining DRG nerve cells.

PTC Therapeutics Provides an Update on Commercial Progress and R&D Pipeline at 42nd Annual J.P. Morgan Healthcare Conference

SOUTH PLAINFIELD, N.J., Jan. 8, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. 

FDA meeting for vatiquinone to discuss how the MOVE-FA data along with additional clinical and preclinical data could support an NDA submission in FA is scheduled for the first quarter. 

Scientific advice feedback from the EMA on a potential submission of vatiquinone for conditional marketing authorization for Friedreich ataxia is expected in the first quarter.

Perspectives of the Friedreich ataxia community on gene therapy clinical trials

Shandra J. Trantham,Mackenzi A. Coker,Samantha Norman,Emma Crowley,Julie Berthy,Barry J. Byrne,Sub Subramony,XiangYang Lou,Manuela Corti; Molecular Therapy Methods & Clinical Development, Volume 32, Issue 1, 101179, doi:10.1016/j.omtm.2023.101179 

 This study provides valuable information on priorities, beliefs, and expectations regarding gene therapy and serves to guide future gene therapy opinion studies and gene therapy trial design.

Omaveloxolone ameliorates isoproterenol-induced pathological cardiac hypertrophy in mice

Xianchao Li, Yang Wu, Yunzhao Yang, Yaohua Wu, Xi Yu & Wenjuan Hu (2023) Omaveloxolone ameliorates isoproterenol-induced pathological cardiac hypertrophy in mice, Free Radical Research, DOI: 10.1080/10715762.2023.2299359 

The cardioprotective effect of omaveloxolone was directly related to the activation of the Nrf2 signaling. In summary, our study identified that omaveloxolone may be a promising therapeutic agent to mitigate pathological cardiac hypertrophy.