Absence of functional deficits in rats following systemic administration of an AAV9 vector despite moderate peripheral nerve and dorsal root ganglia findings: a clinically silent peripheral neuropathy

Cheryl Tyszkiewicz, Seo-Kyoung Hwang, Jamie K. DaSilva, Ramesh C. Kovi, Kelly A. Fader, Madhu P. Sirivelu, June Liu, Chris Somps, Jon Cook, Chang-Ning Liu, Helen Wang, Absence of functional deficits in rats following systemic administration of an AAV9 vector despite moderate peripheral nerve and dorsal root ganglia findings: a clinically silent peripheral neuropathy, NeuroToxicology, 2024, ISSN 0161-813X, doi:10.1016/j.neuro.2024.02.001. 

 These findings demonstrate that there is no detectable functional consequence to the minimal-to-moderate neurodegeneration observed with our AAV9 vector treatment in rats, suggesting a functional tolerance or reserve for loss of DRG neurons after systemic administration of AAV9 vector.

A peptide derived from TID1S rescues frataxin deficiency and mitochondrial defects in FRDA cellular models

Yi Na Dong, Lucie V. Ngaba, Jacob An, Miniat W. Adeshina, Nathan Warren, Jonathan Wong, David R. Lync, Front. Pharmacol. Sec. Neuropharmacology, Volume 15 - 2024, doi: 10.3389/fphar.2024.1352311  

The study of frataxin protein regulation might yield new approaches for FRDA treatment. Here, we report tumorous imaginal disc 1 (TID1), a mitochondrial J-protein cochaperone, as a binding partner of frataxin that negatively controls frataxin protein levels. TID1 interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Acute and subacute depletion of frataxin using RNA interference markedly increases TID1 protein levels in multiple cell types. In addition, TID1 overexpression significantly increases frataxin precursor but decreases intermediate and mature frataxin levels in HEK293 cells. In primary cultured human skin fibroblasts, overexpression of TID1S results in decreased levels of mature frataxin and increased fragmentation of mitochondria. This effect is mediated by the last 6 amino acids of TID1S as a peptide made from this sequence rescues frataxin deficiency and mitochondrial defects in FRDA patient-derived cells. Our findings show that TID1 negatively modulates frataxin levels, and thereby suggests a novel therapeutic target for treating FRDA.

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.