Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

Teerapat Rojsajjakul, Juliette J. Hordeaux, Gourav R. Choudhury, Christian J. Hinderer, Clementina Mesaros, James M. Wilson & Ian A. Blair. Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy. Commun Biol 6, 1093 (2023). doi:10.1038/s42003-023-05472-z 

Increasing expression of heart hFXN-M using gene therapy offers a way to prevent early mortality in FRDA. We used rhesus macaque monkeys to test the pharmacology of an adeno-associated virus (AAV)hu68.CB7.hFXN therapy. The advantage of using non-human primates for hFXN-M gene therapy studies is that hFXN-M and monkey FXN-M (mFXN-M) are 98.5% identical, which limits potential immunologic side-effects. 

The dose response is non-linear resulting in a ten-fold increase in monkey heart hFXN-M protein expression with only a three-fold increase in dose of the vector.

PTC Therapeutics Provides Corporate Update and Reports Third Quarter Financial Results

NEWS PROVIDED BY PTC Therapeutics, Inc. , 26 Oct, 2023 

PTC had a type C written-response-only meeting with FDA for vatiquinone for Friedreich ataxia to determine whether the data from the MOVE-FA study would be sufficient to support an NDA for accelerated approval. In their written response, the FDA stated that while they see the value of upright stability as a clinically meaningful endpoint, they believed a confirmatory study would likely be needed to support NDA submission. PTC has requested a follow-up live meeting to address the issues raised by the FDA. PTC is participating in a scientific advice procedure with the EMA to determine if the MOVE-FA data could support a conditional marketing authorization application in the EEA. PTC expects to have the outcome of this procedure in the first quarter of 2024.

Friedreich's Ataxia-Health Index Development and Validation of a Novel Disease-Specific Patient-Reported Outcome Measure

Friedreich's Ataxia-Health Index Development and Validation of a Novel Disease-Specific Patient-Reported Outcome Measure, Jamison Seabury, Spencer Rosero, Anika Varma, Jennifer Weinstein, Charlotte Engebrecht, Nuran Dilek, John Heatwole, Danae Alexandrou, Brittany Cohen, Jane Larkindale, David R. Lynch, Courtney Park, Sub H. Subramony, Ellen Wagner, Susan Walther, McKenzie Wells, Christine Zizzi, Chad Heatwole Neurol Clin Pract Oct 2023, 13 (5) e200180; DOI: 10.1212/CPJ.0000000000200180 

 Participants with FA identified 18 symptomatic themes of importance to be included as subscales in the FA-HI. The FA-HI demonstrates high internal consistency and test-retest reliability, and it was identified by participants as highly relevant, comprehensive, and easy to complete. FA-HI total and subscale scores statistically differentiated between subgroups of participants with varying levels of disease burden.

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia Francesca Sciarretta, Fabio Zaccaria, Andrea Ninni, Veronica Ceci, Riccardo Turchi, Savina Apolloni, Martina Milani, Ilaria Della Valle, Marta Tiberi, Valerio Chiurchiù, Nadia D’Ambrosi, Silvia Pedretti, Nico Mitro, Katia Aquilano, Daniele Lettieri-Barbato bioRxiv 2023.10.18.562916; doi:10.1101/2023.10.18.562916 

 The study also pinpointed Hcar2 (GPR109A) as a potential agent for butyrate anti-inflammatory impact on microglia. Tests on FRDA mice highlighted the neuroprotective attributes of butyrate intake, bolstering neuromotor performance. In essence, our findings shed light on how cerebellar microglia activation contributes to FRDA and highlight butyrate potential to alleviate neuroinflammation, rectify metabolic imbalances, and boost neuromotor capabilities in FRDA and similar conditions.

Effectiveness of rehabilitation intervention in persons with Friedreich ataxia

Gabriella Paparella, Cristina Stragà, Marinela Vavla, Nicola Pesenti, Vasco Merotto, Gian A. Martorel, Sara Zalunardo, Maria Armellin, Jimmy Comiotto, Andrea Martinuzzi; Effectiveness of rehabilitation intervention in persons with Friedreich ataxia. Front. Neurol. Sec. Neurorehabilitation Volume 14 - 2023 | doi: 10.3389/fneur.2023.1270296 

Our study shows significant functional improvement in all the outcome measures used, except for NHPT bilaterally. FARS and SARA scores post-IR are significatively reduced when compared. 

We demonstrate that IR programs in FRDA can provide a meaningful clinical improvement in terms of outcome measures. These findings could be useful when approaching progressive neurological disorders.

Management of Friedreich's Ataxia-Associated Cardiomyopathy in Pregnancy: A Review of the Literature

Ashleigh N. Peterson, Leigh C. Hickerson, E. Rebecca Pschirrer, Lynsy B. Friend, Cynthia C. Taub, Management of Friedreich's Ataxia-Associated Cardiomyopathy in Pregnancy: A Review of the Literature, The American Journal of Cardiology, 2023, doi:10.1016/j.amjcard.2023.10.019. 

 Most patients with FRDA can deliver vaginally, and neuraxial analgesia is recommended during labor due to the risks associated with general anesthesia. Breastfeeding is encouraged, even for those taking cardiac medications.

Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich´s Ataxia

Elisabetta Indelicato, Klaus Faserl, Matthias Amprosi, Wolfgang Nachbauer, Rainer Schneider, Julia Wanschitz, Bettina Sarg, Sylvia Boesch. Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich´s Ataxia; Front. Neurosci. Sec. Neuropharmacology Volume 17 - 2023 | doi: 10.3389/fnins.2023.1289027. 

Principal component analysis showed a clear separation between FRDA and control samples. Interactome analysis revealed clustering of DE proteins in oxidative phosphorylation, ribosomal elements, mitochondrial architecture control and fission/fusion pathways. DE findings in the muscle-specific proteomics suggested a shift towards fasttwitching glycolytic fibers. Notably, most DE proteins (169/228, 74%) are target of the transcription factor nuclear factor-erythroid 2.Our data corroborate a mitochondrial biosignature of FRDA, which extends beyond a mere oxidative phosphorylation failure. Skeletal muscle proteomics highlighted a derangement of mitochondrial architecture and maintenance pathways and a likely adaptive metabolic shift of contractile proteins.The present findings are relevant for the design of future therapeutic strategies and highlight the value of skeletal muscle -omics as disease state readout in FRDA.

Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich´s Ataxia

Correction to Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study)

Lynch D. Correction to Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol. 2023 Oct 5. doi: 10.1002/ana.26808. Epub ahead of print. Erratum for: Ann Neurol. 2021 Feb;89(2):212-225. PMID: 37795909.

 In the Results section, the text should read: “Within the mFARS assessment, omaveloxolone improved each component (bulbar, upper limb coordination, lower limb coordination, and upright stability) relative to placebo, although the greatest effects were on upper limb coordination, followed by upright stability.

Disease Delineation for Multiple Sclerosis, Friedreich Ataxia, and Healthy Controls Using Supervised Machine Learning on Speech Acoustics

Schultz BG, Joukhader Z, Nattala U, et al. Disease Delineation for Multiple Sclerosis, Friedreich Ataxia, and Healthy Controls Using Supervised Machine Learning on Speech Acoustics. IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. 2023 Oct;PP. DOI: 10.1109/tnsre.2023.3321874. PMID: 37792655.

 Results showed that Friedreich ataxia, multiple sclerosis and healthy controls were all identified with high accuracy (over 82%). Twenty-one acoustic features were strong markers of neurodegenerative diseases, falling under the categories of spectral qualia, spectral power, and speech rate. We demonstrated that speech markers can delineate neurodegenerative diseases and distinguish healthy speech from pathological speech with high accuracy.

Vestibular Pathology as Early Finding of Friedreich’s Ataxia in a 16 Years Old Woman

Fernández, A.G. Vestibular Pathology as Early Finding of Friedreich’s Ataxia in a 16 Years Old Woman. Indian J Otolaryngol Head Neck Surg (2023). doi:10.1007/s12070-023-04249-4 

Friedreich’s ataxia is degenerative disease frequently starting around puberty and it’s characterized by a progressive gait ataxia, limb weakness, apparition of Babinsky sign, loss of deep tendon reflex, dysarthria and skeletal deformities. The development of vestibular pathology is common but not completely understood. A 16 years old woman with early vestibular defects in relation to a latter Friedreich’s ataxia diagnosis is reported.