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.

Omaveloxolone approved for patients aged 16 years and older with Friedreich ataxia (FRDA): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG)

Arthur Lenahan, Sho Yano, Brett Graham, Kuntal Sen, Omaveloxolone approved for patients aged 16 years and older with Friedreich ataxia (FRDA): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG), Genetics in Medicine Open, Volume 1, Issue 1, 2023, 100832, ISSN 2949-7744, doi:10.1016/j.gimo.2023.100832. 

Omaveloxolone (trade name: SKYCLARYS) is a Nrf2 activator that increases cellular resilience to oxidative stress that has been FDA approved for patients with FRDA who are 16 years and older. Omaveloxolone received orphan drug, fast track, priority review, and rare pediatric disease designations. Omaveloxolone is a semisynthetic triterpenoid administered orally once daily.

CO105 A Retrospective Study Characterizing Age at Loss of Ambulation Among Patients With Friedreich Ataxia Using Health Administrative Claims Data in the United States

A. Salvucci, C. Qian, L. Powell, D. Lynch, G. Vasco, K. Johnston, I. Tomazos, CO105 A Retrospective Study Characterizing Age at Loss of Ambulation Among Patients With Friedreich Ataxia Using Health Administrative Claims Data in the United States, Value in Health, Volume 26, Issue 12, Supplement, 2023, Pages S33-S34, ISSN 1098-3015, doi:10.1016/j.jval.2023.09.177. 

 In this cross-sectional analysis, most patients who were diagnosed with FA before the ages of 24 years experienced LOA and wheelchair use before the age of 16 years. While limitations exist in ascertainment of LOA using claims data, findings suggest that those who had earlier onset of FA also had earlier LOA.

Mitochondrial impairment, decreased sirtuin activity and protein acetylation in dorsal root ganglia in Friedreich Ataxia models

Arabela Sanz-Alcázar, Elena Britti, Fabien Delaspre, Marta Medina-Carbonero, Maria Pazos-Gil, Jordi Tamarit, Joaquim Ros & Elisa Cabiscol​. Mitochondrial impairment, decreased sirtuin activity and protein acetylation in dorsal root ganglia in Friedreich Ataxia models. Cell. Mol. Life Sci. 81, 12 (2024). doi:10.1007/s00018-023-05064-4 

 The NAD+/NADH ratio was reduced and sirtuin activity was impaired. We identified alpha tubulin as the major acetylated protein from DRG homogenates whose levels were increased in FXNI151F mice compared to WT mice. In the mitochondria, superoxide dismutase (SOD2), a SirT3 substrate, displayed increased acetylation in frataxin-deficient DRG neurons. Since SOD2 acetylation inactivates the enzyme, and higher levels of mitochondrial superoxide anion were detected, oxidative stress markers were analyzed. Elevated levels of hydroxynonenal bound to proteins and mitochondrial Fe2+ accumulation was detected when frataxin decreased. Honokiol, a SirT3 activator, restores mitochondrial respiration, decreases SOD2 acetylation and reduces mitochondrial superoxide levels. Altogether, these results provide data at the molecular level of the consequences of electron transport chain dysfunction, which starts negative feedback, contributing to neuron lethality. This is especially important in sensory neurons which have greater susceptibility to frataxin deficiency compared to other tissues.

Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study

Indelicato, E., Reetz, K., Maier, S., Nachbauer, W., Amprosi, M., Giunti, P., Mariotti, C., Durr, A., de Rivera Garrido, F.J.R., Klopstock, T., Schöls, L., Klockgether, T., Bürk, K., Pandolfo, M., Didszun, C., Grobe-Einsler, M., Nanetti, L., Nenning, L., Kiechl, S., Dichtl, W., Ulmer, H., Schulz, J.B., Boesch, S. and (2023), Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study. Mov Disord. doi:10.1002/mds.29687 

Arrhythmias, progressive neurological disability, and diabetes mellitus influence the overall survival in FA. We built a survival prognostic score which identifies patients meriting closer surveillance and who may benefit from early invasive cardiac monitoring and therapy.