Spinal cord damage in Friedreich's ataxia: Results from ENIGMA-Ataxia

Thiago JR Rezende, Isaac M Adanyeguh, Filippo Arrigoni, Benjamin Bender, Fernando Cendes, Louise A Corben, Andreas Deistung, Martin Delatycki, Imis Dogan, Gary Egan, Sophia L Goricke, Nellie Georgiou-Karistianis, Pierre-Gilles Henry, Diane Hutter, Neda Jahanshad, James M Joers, Christophe Lenglet, Tobias Lindig, Alberto RM Martinez, Andrea Martinuzzi, Gabriella Paparella, Denis Peruzzo, Kathrin Reetz, Sandro Romanzetti, Ludger Schols, Jorg B Schulz, Matthis Synofzik, Sophia I Thomopoulos, Paul M Thompson, Dagmar Timmann, Ian H Harding, Marcondes C Franca Jr.; medRxiv 2022.04.20.22273878; doi: 10.1101/2022.04.20.22273878

Interpretation: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage or both. Hence, our data support the hypothesis that damage to DC and CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, whereas CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression.

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

Tastan B, Arioz BI, Genc S.;Frontiers in Immunology. 2022 ;13:865772. DOI: 10.3389/fimmu.2022.865772. PMID: 35418995; PMCID: PMC8995746. 

 In this review, current knowledge on NLRP3 inflammasome activation and Nrf2 pathways is presented; the relationship between NLRP3 inflammasome signaling and Nrf2 pathway, as well as the pre/clinical use of Nrf2 activators against NLRP3 inflammasome activation in disorders of the central nervous system, are thoroughly described. Cumulative evidence points out therapeutic use of Nrf2 activators against NLRP3 inflammasome activation or diseases that NLRP3 inflammasome contributes to would be advantageous to prevent inflammatory conditions; however, the side effects of these molecules should be kept in mind before applying them to clinical practice.

Phase IA Study of AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT05302271; Recruitment Status : Recruiting; First Posted : March 31, 2022 Sponsor: Weill Medical College of Cornell University 

The purpose of this study is to test the safety and preliminary efficacy of AAVrh.10hFXN to treat the cardiomyopathy associated with Friedreich's ataxia (FA). AAVrh.10hFXN is a serotype rh.10 adeno-associated virus gene transfer vector coding for Frataxin (FXN). The drug is administered intravenously. This is a phase 1, open label, dose escalation study with a total of 10 participants. Drug: Prednisone, all participants will remain immunosuppression therapy with prednisone for a total of 14 weeks.

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

Norrish G, Rance T, Montanes E, et al.; Archives of Disease in Childhood 2022;107:450-455. 

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.

The smoothened agonist SAG reduces mitochondrial dysfunction and neurotoxicity of frataxin-deficient astrocytes

Andrés Vicente-Acosta, Alfredo Giménez-Cassina, Javier Díaz-Nido and Frida Loria; J Neuroinflammation 19, 93 (2022). doi:10.1186/s12974-022-02442-w

Furthermore, in vitro culture of neurons with conditioned medium from frataxin-deficient astrocytes results in a reduction of neuronal survival, neurite length and synapse formation. However, when frataxin-deficient astrocytes were chronically treated with SAG, we did not observe these alterations in neurons.

Yeast cells depleted of the frataxin homolog Yfh1 redistribute cellular iron: studies using Mössbauer spectroscopy and mathematical modeling

Fernandez, Salvador et al., Journal of Biological Chemistry, Volume 0, Issue 0, 101921, doi:10.1016/j.jbc.2022.101921

 Simulations suggested partially independent regulation in which cellular iron import is regulated by ISC activity in mitochondria, mitochondrial iron import is regulated by a mitochondrial FeII pool, and vacuolar iron import is regulated by cytosolic FeII and mitochondrial ISC activity.

Serum glial fibrillary acidic protein is a body fluid biomarker: A valuable prognostic for neurological disease – A systematic review

Luana Heimfarth, Fabiolla Rocha Santos Passos, Brenda Souza Monteiro, Adriano Antunes de Souza Araújo, Lucindo José Quintans Júnior, Jullyana de Souza Siqueira Quintans, International Immunopharmacology, Volume 107, 2022, 108624, ISSN 1567-5769, doi:10.1016/j.intimp.2022.108624. 

Astrocytes are the most abundant cell type in the human central nervous system, and they play an important role in the regulation of neuronal physiology. In neurological disorders, astrocyte disintegration leads to the release of glial fibrillary acidic protein (GFAP) from tissue into the bloodstream. Elevated serum levels of GFAP can serve as blood biomarkers, and a useful prognostic tool to facilitate the early diagnosis of several neurological diseases ranging from stroke to neurodegenerative disorders. This systematic review synthesizes studies published between January 2012 and September 2021 that used GFAP as a potential blood biomarker to detect neurological disorders. The following electronic databases were accessed: MEDLINE, Scopus, and Web of Science. In all the databases, the following search strategy was used: ¨GFAP¨ OR ¨glial fibrillary acidic protein¨ AND ¨neurological¨ OR ¨neurodegenerative¨ AND ¨plasma¨ OR ¨serum¨. The initial search identified 1152 articles. After the exclusion criteria were applied, 48 publications that reported GFAP levels in neurological disorders were identified. A total of16 different neurological disorders that have plasmatic GFAP levels as a possible biomarker for the disease were described in the articles, being: multiple sclerosis, frontotemporal lobar degeneration, Alzheimer’s disease, Parkinson disease, COVID-19, epileptic seizures, Wilson Disease, diabetic ketoacidosis, schizophrenia, autism spectrum disorders, major depressive disorder, glioblastoma, spinal cord injury, asthma, neuromyelitis optica spectrum disorder and Friedreich’s ataxia. Our review shows an association between GFAP levels and the disease being studied, suggesting that elevated GFAP levels are a potentially valuable diagnostic biomarker in the evaluation of different neurological diseases.

DNA methylation in Friedreich ataxia silences expression of frataxin isoform E

Layne N. Rodden, Kaitlyn M. Gilliam, Christina Lam, Teerapat Rojsajjakul, Clementina Mesaros, Chiara Dionisi, Mark Pook, Massimo Pandolfo, David R. Lynch, Ian A. Blair & Sanjay I. Bidichandani. Sci Rep 12, 5031 (2022). https://doi.org/10.1038/s41598-022-09002-5 

A lesser known extramitochondrial isoform of frataxin detected in erythrocytes, frataxin-E, is encoded via an alternate transcript (FXN-E) originating in intron 1 that lacks a mitochondrial targeting sequence. We show that FXN-E is deficient in FRDA, including in patient-derived cell lines, iPS-derived proprioceptive neurons, and tissues from a humanized mouse model. In a series of FRDA patients, deficiency of frataxin-E protein correlated with the length of the expanded GAA triplet-repeat, and with repeat-induced DNA hypermethylation that occurs in close proximity to the intronic origin of FXN-E. CRISPR-induced epimodification to mimic DNA hypermethylation seen in FRDA reproduced FXN-E transcriptional deficiency. Deficiency of frataxin E is a consequence of FRDA-specific epigenetic silencing, and therapeutic strategies may need to address this deficiency.

Design Therapeutics Completes Dosing in First Patient Cohort of Phase 1 Trial of DT-216 GeneTAC™ Molecule for the Treatment of Friedreich Ataxia

CARLSBAD, Calif., March 30, 2022 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for degenerative genetic disorders, today announced that it has completed dosing in the first single ascending dose (SAD) cohort of its Phase 1 clinical trial of DT-216 in patients with Friedreich ataxia (FA). DT-216 is a novel GeneTAC™ gene targeted chimera small molecule designed to specifically target the GAA repeat expansion mutation, the underlying cause of FA, and restore frataxin (FXN) gene expression. Additionally, Design announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to DT-216 for the treatment of patients with FA.

Reata Pharmaceuticals Completes Rolling Submission of New Drug Application for Omaveloxolone for the Treatment of Patients with Friedreich’s Ataxia

PLANO, Texas--(BUSINESS WIRE)-- Reata Pharmaceuticals, Inc. (Nasdaq: RETA), (“Reata,” the “Company,” “our,” “us,” or “we”), a clinical-stage biopharmaceutical company, today announced the completion of the rolling submission of a New Drug Application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) for omaveloxolone for the treatment of patients with Friedreich’s ataxia. This NDA is supported by the efficacy and safety data from the MOXIe Part 1, Part 2, and MOXIe Extension studies. The FDA has granted Fast Track Designation and Orphan Drug Designation to omaveloxolone for the treatment of Friedreich’s ataxia.