Neuroinflammation in the Cerebellum and Brainstem in Friedreich Ataxia: An [18F]-FEMPA PET Study

Khan, W., Corben, L.A., Bilal, H., Vivash, L., Delatycki, M.B., Egan, G.F. and Harding, I.H. (2021), Mov Disord. doi:10.1002/mds.28825 

Neuroinflammation is evident in brain regions implicated in FRDA neuropathology. Increased neuroimmune activity may be related to earlier disease onset and attenuate over the course of the illness.

Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study

Norrish G, Rance T, Montanes E, Field E, Brown E, Bhole V, Stuart G, Uzun O, McLeod KA, Ilina M, Adwani S, Daubeney P, Delle Donne G, Linter K, Jones CB, Bharucha T, Cervi E, Kaski JP.; Arch Dis Child. 2021 Oct 5:archdischild-2021-322455. doi: 10.1136/archdischild-2021-322455. Epub ahead of print. PMID: 34610949. 

This is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly.

Highlighting the Significant Strides Made in Friedreich Ataxia Care

NeurologyLive. October 1, 2021. David R. Lynch, MD, PhD, professor of neurology, University of Pennsylvania Perelman School of Medicine, discussed why omaveloxolone’s recent success speaks to the progress made within the FA treatment space.

Reata Pharmaceuticals Plans NDA Submission for Omaveloxolone in First Quarter of 2022 Following Completion of Pre-NDA Meeting with FDA

September 30, 2021. PLANO, Texas--(BUSINESS WIRE)--Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” or “we”), a clinical-stage biopharmaceutical company, today announced that it has completed its pre-New Drug Application (“NDA”) meeting with the United States Food and Drug Administration (“FDA”) for omaveloxolone for the treatment of patients with Friedreich’s ataxia and reaffirmed its plan to submit an NDA in the first quarter of 2022.

A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation

Li Li, Devon M. Conradson, Vinita Bharat, Min Joo Kim, Chung-Han Hsieh, Paras S. Minhas, Amanda M. Papakyrikos, Aarooran Sivakumaran Durairaj, Anthony Ludlam, Katrin I. Andreasson, Linda Partridge, Michael A. Cianfrocco & Xinnan Wang; Nature Metabolism. 2021 Sep;3(9):1242-1258. DOI: 10.1038/s42255-021-00443-2. PMID: 34504353. 

 Cysteine oxidation of MIC60, an inner mitochondrial membrane protein, triggers the formation of disulfide bonds and the physical association of MIC60 with Miro, an outer mitochondrial membrane protein. The oxidative structural change of this membrane-crossing complex ultimately elicits cellular responses that delay mitophagy, impair cellular respiration and cause oxidative stress. Blocking the MIC60–Miro interaction or reducing either protein, genetically or pharmacologically, extends lifespan and health-span of healthy fruit flies, and benefits multiple models of Parkinson’s disease and Friedreich’s ataxia. Our discovery provides a molecular basis for common treatment strategies against oxidative stress.

Adaptation of the heart to Frataxin depletion: Evidence that integrated stress response can predominate over mTORC1 activation

César Vásquez-Trincado, Monika Patel, Aishwarya Sivaramakrishnan, Carmen Bekeová, Lauren Anderson-Pullinger, Nadan Wang, Hsin-Yao Tang, Erin L Seifert, Human Molecular Genetics, 2021;, ddab216, doi:10.1093/hmg/ddab216

Altogether, these findings suggest that the FXN depleted heart can suppress a major ATP demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.

Microvascular Breakdown Due to Retinal Neurodegeneration in Ataxias

Christopher A. Turski MD, Gabrielle N. Turski MD, Jennifer Faber MD, Stefan J. Teipel MD, Frank G. Holz MD, Thomas Klockgether MD, Robert P. Finger MD; Mov Disord. (2021), doi:10.1002/mds.28791

These findings demonstrate a distinct pattern of concurrent changes in vessel density of the retinal superficial vascular complex, encompassing the superficial vascular plexus, RPC network and cdONH, and retinal GCL volume, providing new insights into the ongoing degeneration in ataxias. Our findings may have relevance for design of novel therapeutic approaches for ataxias and possibly other neurodegenerative diseases.

The temporal dynamics of the DMN state also correlated with minute-long DMN rsFC

Naeije G, Coquelet N, Wens V, et al. . Human Brain Mapping. 2021 Sep. DOI: 10.1002/hbm.25621. PMID: 34523778. ; This study demonstrates that ASO is the main determinant of alterations in the sub-second dynamics of posterior associative neocortices in FRDA patients and substantiates a direct link between sub-second network activity and functional brain integration over long timescales.

Blood Neurofilament Light Chain in Genetic Ataxia: A Meta-Analysis

Peng L, Wang S, Chen Z, Peng Y, Wang C, Long Z, Peng H, Shi Y, Hou X, Lei L, Wan L, Liu M, Zou G, Shen L, Xia K, Qiu R, Tang B, Ashizawa T, Klockgether T, Jiang H.; Mov Disord. 2021 Sep 14. doi: 10.1002/mds.28783. Epub ahead of print. PMID: 34519102. 

 bNfL can be used as a potential biomarker to predict disease onset, severity, and progression of genetic ataxia. Reference-value setting of bNfL should be divided according to age

Plasma idebenone monitoring in Friedreich's ataxia patients during a long-term follow-up

Paredes-Fuentes AJ, Cesar S, Montero R, Latre C, Genovès J, Martorell L, Cuadras D, Colom H, Pineda M, Del Mar O'Callaghan M, Sarquella-Brugada G, Darling A, Artuch R.; Biomed Pharmacother. 2021 Sep 7;143:112143. doi: 10.1016/j.biopha.2021.112143. Epub ahead of print. PMID: 34507114. 

The large variations observed among the different individuals involved in this study should be considered for optimization of individual dosage regimens.